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The main results of the present study are as follows: 1) breathing gas mixtures containing 2% or 4% CO2significantly attenuated bronchoconstrictor responses to methacholine, not differently in healthy subjects and subjects with mild asthma, and 2) the causal inhibitory effect of CO2was significantly mediated via an indirect effect of the increment of V̇e in response to intrapulmonary hypercapnia.

The forced oscillation technique can identify a surrogate of closing volume (CVFOT). We investigated its relationship with the one measured by single-breath washout (CVSBW). CVFOT weakly correlates with CVSBW. The respective closing capacities were correlated, but their increases after methacholine challenge in asthmatics did not. Our results suggest that CVFOT is less sensitive than CVSBW to few flow-limited/closed airways but more specific in detecting increases in flow-limited/closed airways involving the majority of the lung.

Pulmonary electrical impedance tomography (EIT) is a functional imaging technique that allows real-time monitoring of ventilation distribution. Ventilation heterogeneity (VH) is a characteristic feature of chronic obstructive pulmonary disease (COPD) and has previously been quantified using features derived from tidal variations in the amplitude of the EIT signal. However, VH may be better described by time-based metrics, the measurement of which is made possible by the high temporal resolution of EIT. We aimed 1) to quantify VH using novel time-based EIT metrics and 2) to determine the physiological relevance of these metrics by exploring their relationships with complex lung mechanics measured by the forced oscillation technique (FOT). We performed FOT, spirometry, and tidal-breathing EIT measurements in 11 healthy controls and 9 volunteers with COPD. Through offline signal processing, we derived 3 features from the impedance-time ( Z- t) curve for each image pixel: 1) tE, mean expiratory time; 2) PHASE, mean time difference between pixel and global Z- t curves; and 3) AMP, mean amplitude of Z- t curve tidal variation. Distribution was quantified by the coefficient of variation (CV) and the heterogeneity index (HI). Both CV and HI of the tE and PHASE features were significantly increased in COPD compared with controls, and both related to spirometry and FOT resistance and reactance measurements. In contrast, distribution of the AMP feature showed no relationships with lung mechanics. These novel time-based EIT metrics of VH reflect complex lung mechanics in COPD and have the potential to allow real-time visualization of pulmonary physiology in spontaneously breathing subjects. NEW & NOTEWORTHY Pulmonary electrical impedance tomography (EIT) is a real-time imaging technique capable of monitoring ventilation with exquisite temporal resolution. We report novel, time-based EIT measurements that not only demonstrate ventilation heterogeneity in chronic obstructive pulmonary disease (COPD), but also reflect oscillatory lung mechanics. These EIT measurements are noninvasive, radiation-free, easy to obtain, and provide real-time visualization of the complex pathophysiology of COPD.

Respiratory system reactance (Xrs) measured by the forced oscillation technique (FOT) is theoretically and experimentally related to lung volume. In chronic obstructive pulmonary disease (COPD), the absolute volume measured by body plethysmography includes a proportion that is inaccessible to pressure oscillations applied via the mouth, that is, a “noncommunicating” lung volume. We hypothesized that in COPD the presence of noncommunicating lung would disrupt the expected Xrs-volume relationship compared with plethysmographic functional residual capacity (FRCpleth). Instead, Xrs would relate to estimates of communicating volume, namely, expiratory reserve volume (ERV) and single-breath alveolar volume (VaSB). We examined FOT and lung function data from people with COPD ( n = 51) and from healthy volunteers ( n = 40). In healthy volunteers, we observed an expected inverse relationship between reactance at 5 Hz (X5) and FRCpleth. In contrast, there was no such relationship between X5 and FRCpleth in COPD subjects. However, there was an inverse relationship between X5 and both ERV and VaSB. Hence the theoretical Xrs-volume relationship is present in COPD but only when considering the communicating volume rather than the absolute lung volume. These findings confirm the role of reduced communicating lung volume as an important determinant of Xrs and therefore advance our understanding and interpretation of FOT measurements in COPD. NEW & NOTEWORTHY To investigate the determinants of respiratory system reactance (Xrs) measured by the forced oscillation technique (FOT) in chronic obstructive pulmonary disease (COPD), we examine the relationship between Xrs and lung volume. We show that Xrs does not relate to absolute lung volume (functional residual capacity) in COPD but instead relates only to the volume of lung in communication with the airway opening. This communicating volume may therefore be fundamental to our interpretation of FOT measurements in COPD and other pulmonary diseases.

The measurement of lung function in mice and rats is crucial for understanding how well small animal models of pulmonary disease recapitulate human clinical pathology but brings with it the challenge of making accurate measurements in animals as small as a mouse. Overcoming these challenges can be achieved in a number of ways, each based on a model idealization of how the lung works as a mechanical system. Accordingly, it is important to understand the theoretical basis on which an assessment of lung function rests to interpret experimental measurements appropriately. It is also crucial to attend to a number of practical issues that determine the quality of the measurements. The most accurate measurements of lung function in small animals are provided by the forced oscillation technique that provides lung resistance and elastance and its multifrequency generalization known as impedance. Measurement quality is maximized when the greatest possible degree of control is exerted over the amplitude and frequency with which air is oscillated in and out of the lungs, the mean or end-expiratory transpulmonary pressure pertaining to when the oscillations are applied, and the immediate past volume history of the lungs. It is also crucial that no spontaneous breathing efforts occur during the measurement period. Finally, there is no substitute for the skill in animal handling and surgical preparation that comes with practice; such a skill should be in place before embarking on any important series of experiments.

Obesity is associated with important decrements in lung volumes. Despite this, ventilation remains normally or near normally distributed at least for moderate decrements in functional residual capacity (FRC). We tested the hypothesis that this is because maximum flow increases presumably as a result of an increased lung elastic recoil. Forced expiratory flows corrected for thoracic gas compression volume, lung volumes, and forced oscillation technique at 5–11–19 Hz were measured in 133 healthy subjects with a body mass index (BMI) ranging from 18 to 50 kg/m2. Short-term temporal variability of ventilation heterogeneity was estimated from the interquartile range of the frequency distribution of the difference in inspiratory resistance between 5 and 19 Hz (R5–19_IQR). FRC % predicted negatively correlated with BMI ( r = −0.72, P < 0.001) and with an increase in slope of either maximal ( r = −0.34, P < 0.01) or partial flow-volume curves ( r = −0.30, P < 0.01). Together with a slight decrease in residual volume, this suggests an increased lung elastic recoil. Regression analysis of R5–19_IQRagainst FRC % predicted and expiratory reserve volume (ERV) yielded significantly higher correlation coefficients by nonlinear than linear fitting models ( r2= 0.40 vs. 0.30 for FRC % predicted and r2= 0.28 vs. 0.19 for ERV). In conclusion, temporal variability of ventilation heterogeneities increases in obesity only when FRC falls approximately below 65% of predicted or ERV below 0.6 liters. Above these thresholds distribution is quite well preserved presumably as a result of an increase in lung recoil.

The double sigmoidal nature of the mouse pressure-volume (PV) curve is well recognized but largely ignored. This study systematically examined the effect of inflating the mouse lung to 40 cm H2O transrespiratory pressure (Prs) in vivo. Adult BALB/c mice were anesthetized, tracheostomized, and mechanically ventilated. Thoracic gas volume was calculated using plethysmography and electrical stimulation of the intercostal muscles. Lung mechanics were tracked during inflation-deflation maneuvers using a modification of the forced oscillation technique. Inflation beyond 20 cm H2O caused a shift in subsequent PV curves with an increase in slope of the inflation limb and an increase in lung volume at 20 cm H2O. There was an overall decrease in tissue elastance and a fundamental change in its volume dependence. This apparent “softening” of the lung could be recovered by partial degassing of the lung or applying a negative transrespiratory pressure such that lung volume decreased below functional residual capacity. Allowing the lung to spontaneously recover revealed that the lung required ∼1 h of mechanical ventilation to return to the original state. We propose a number of possible mechanisms for these observations and suggest that they are most likely explained by the unfolding of alveolar septa and the subsequent redistribution of the fluid lining the alveoli at high transrespiratory pressure.

Using the forced oscillation technique, we tracked airway resistance continuously during quiet breathing (QB) and deep inspiration (DI), thus observing fluctuations in resistance that may reflect mechanisms of airway stretch and renarrowing. After DI, however, the resistance may be depressed for a period not related to volume changes. We hypothesized that this gradual increase in resistance after DI-induced dilation was determined by a simple time constant. Furthermore, to the extent that this effect reflects dynamic characteristics of airway renarrowing, the resistance change after each tidal inspiration should also be constrained by this temporal limit. A model relating resistance fluctuations to the breathing pattern, including both instantaneous and delayed effects, was developed and applied to data from 14 nonasthmatic and 17 asthmatic subjects (forced expiratory volume in 1 s = 103 ± 13 and 83 ± 12%, respectively, means ± SD) after methacholine challenge (dose 145 ± 80 and 3.0 ± 3.4 μmol, respectively) that resulted in respective forced expiratory volume in 1 s reductions of 16 ± 7 and 24 ± 6% from baseline. Resistance was measured continuously for 1 min of QB, a DI, followed by a further minute of QB. Resistance values at end expiration (Ree) and end inspiration were calculated. We found that the sequence of Ree after DI was best modeled by a power-law function of time rather than an exponential decay ( r2= 0.82 ± 0.18 compared with 0.63 ± 0.16; P < 0.01). Furthermore, the coefficient characterizing this “renarrowing function” was close to equal to the coefficient characterizing the equivalent function of resistance change between each resistance value at end inpiration and subsequent Ree during QB, particularly in the nonasthmatic subjects for whom the intraclass correlation was 0.66. This suggests that the same time-dependent factors determine renarrowing after both large and small breaths.

To more precisely measure the mechanical properties of the lung periphery in asthma, we have developed a forced oscillation technique that applies a broad-band flow signal through a wedged bronchoscope. We interpreted the data from four healthy and eight mildly asthmatic subjects in terms of an anatomically accurate computer model of the wedged segment. There was substantial overlap in impedance between the two groups, with resistance (R) showing minimal frequency dependence and elastance (E) showing positive and negative frequency dependence across subjects. After direct instillation of methacholine, R rose in both groups, but compared with healthy subjects, the asthmatic subjects displayed upward, parallel shifts in their dose-response curves. The baseline frequency-response patterns of E were enhanced after methacholine. Frequency dependencies of R and E were well reproduced in two normal subjects by a computational model that employed rigid airways connected to constant-phase tissue units but were better reproduced in the other two normal and three asthmatic subjects when the model employed heterogeneous, peripheral airway narrowing and compliant airways. To capture the frequency dependencies of R and E in the remaining five asthmatic subjects, the model was modified by increasing airway wall stiffness. These results indicate that the lung periphery of mildly asthmatic subjects is not well distinguished from that of healthy subjects by measurement of mechanical impedance at baseline, but group differences are seen after challenge with methacholine. Modeling of the response suggests that variable contributions of airway narrowing and wall compliance are operative in determining overall mechanical impedance of the lung periphery in humans with asthma, likely reflecting the functional consequences of airway inflammation and remodeling.

The beating heart naturally oscillates the lung because of the close juxtaposition between these organs producing cardiogenic oscillations in flow that can be measured at the mouth when the glottis is open. Correspondingly, if the mouth is occluded, the same phenomenon produces cardiogenic pressure oscillations that can be measured just distal to the site of occlusion. The Fourier-domain ratio of these oscillations in pressure and flow constitutes what we call cardiogenic respiratory impedance (Zc). We calculated Zc between about 1.5 and 10 Hz in relaxed normal subjects at functional residual capacity with open glottis. Zc was insensitive to heart rate changes induced by exercise and had an imaginary part close to zero at all frequencies investigated. Its real part was similar to or smaller than resistance determined by the forced oscillation technique. We speculate that Zc measures the flow resistance of the central and upper airways of the lung. Zc may be useful as a means of obtaining information about lung mechanics without the need for an external source of flow perturbations.

When input impedance is determined by means of the forced oscillation technique, part of the oscillatory flow measured at the mouth is lost in the motion of the upper airway wall acting as a shunt. This is avoided by applying the oscillations around the subject’s head (head generator) rather than at the mouth (conventional technique). In seven wheezing infants, we compared both techniques to estimate the importance of the upper airway wall shunt impedance (Zuaw) for the interpretation of the conventional technique results. Computation of Zuaw required, in addition, estimation of nasal impedance values, which were drawn from previous measurements (K. N. Desager, M. Willemen, H. P. Van Bever, W. De Backer, and P. A. Vermeire. Pediatr. Pulmonol. 11: 1–7, 1991). Upper airway resistance and reactance at 12 Hz ranged from 40 to 120 and from 0 to −150 hPa ⋅ l−1 ⋅ s, respectively. Varying nasal impedance within the range observed in infants did not result in major changes in the estimates of Zuaw or lung impedance (Zl), the impedance of the respiratory system in parallel with Zuaw. The conventional technique underestimated Zl, depending on the value of Zuaw. The head generator technique slightly overestimated Zl, probably because the pressure gradient across the upper airway was not completely suppressed. Because of the need to enclose the head in a box (which is not required with the conventional technique), the head generator technique is difficult to perform in infants.

Frey, Urs, Bela Suki, Richard Kraemer, and Andrew C. Jackson. Human respiratory input impedance between 32 and 800 Hz, measured by interrupter technique and forced oscillations. J. Appl. Physiol. 82(3): 1018–1023, 1997.—Respiratory input impedance (Zin) over a wide range of frequencies ( f) has been shown to be useful in determining airway resistance (Raw) and tissue resistance in dogs or airway wall properties in human adults. Zin measurements are noninvasive and, therefore, potentially useful in investigation of airway mechanics in infants. However, accurate measurements of Zin at these f values with the use of forced oscillatory techniques (FOT) in infants are difficult because of their relatively high Raw and large compliance of the face mask. If pseudorandom noise pressure oscillations generated by a loudspeaker are applied at the airway opening (FOT), the power of the resulting flow decreases inversely with f because of capacitive shunting into the volume of the gas in the speaker chamber and in the face mask. We studied whether high-frequency respiratory Zin can be measured by using rapid flow interruption [high-speed interrupter technique (HIT)], in which we expect the flow amplitude in the respiratory system to be higher than in the FOT. We compared Zin measured by HIT with Zin measured by FOT in a dried dog lung and in five healthy adult subjects. The impedance was calculated from two pressure signals measured between the mouth and the HIT valve. The impedance could be assessed from 32 to 800 Hz. Its real part at low f as well as the f and amplitude of the first and second acoustic resonance, measured by FOT and by HIT, were not significantly different. The power spectrum of oscillatory flow when the HIT was used showed amplitudes that were at least 100 times greater than those when FOT was used, increasing at f > 400 Hz. In conclusion, the HIT enables the measurement of high-frequency Zin data ranging from 32 to 800 Hz with particularly high flow amplitudes and, therefore, possibly better signal-to-noise ratio. This is particularly important in systems with high Raw, e.g., in infants, when measurements have to be performed through a face mask.

A noninvasive forced oscillation technique was used to determine respiratory function in unanesthetized and spontaneously breathing mice. Pseudorandom noise pressure variations in a frequency range of 16–208 Hz were applied to the body surface, and the flow response was measured at the nose. From the pressure-flow relationship, respiratory transfer impedance was calculated. Study of intra-animal variability on a short- and a long-term basis revealed that the real part of respiratory transfer impedance was reproducible within 9%. The imaginary part appeared less reproducible (within 22%). Furthermore, bronchoconstrictive responses were investigated and analyzed by evaluation of respiratory resistance as measured at 16 Hz (Rrs16). During the first 15 min after ovalbumin challenge in ovalbumin-sensitized mice, Rrs16 was significantly increased [49 +/- 7% (SE)]. Inhalation of methacholine in untreated mice induced an increase in Rrs16 of 75 +/- 16% (SE). In saline-challenged animals, no significant changes were observed. This method enables evaluation of long-term respiratory function in mice and appeared to be a sensitive measure for bronchoconstriction.

Respiratory mechanics were compared using conventional and forced oscillation techniques in six conscious horses and a mechanical model of the equine respiratory system. The parameters calculated from conventional airflow and esophageal pressure measurements were pulmonary resistance and dynamic compliance. The impedance of the respiratory system was measured at 1, 2, and 3 Hz with the forced oscillation technique, and respiratory system resistance, compliance, inertance, and resonant frequency were calculated. Pulmonary resistance was 1.0 +/- 0.3 cmH2O.l-1.s, and pulmonary dynamic compliance was 2.4 +/- 0.6 l/cmH2O. With the use of the forced oscillation system, respiratory resistance was 1.61 +/- 0.50 cmH2O.l-1.s at 1 Hz, compliance was 0.195 +/- 0.075 l/cmH2O, inertance was 0.026 +/- 0.0095 cmH2O.l-1.s2, and resonant frequency was 2.40 +/- 0.25 Hz. Data collected from a model of the respiratory system showed a close correlation between resistance and compliance measured with the two systems. This study demonstrates that the forced oscillation technique is a useful method for noninvasive measurement of respiratory mechanics in horses.

The input impedance of the lung (Zin) at high frequencies (> 100 Hz) is a complex function of the airway geometry and the mechanical properties of the airway walls. To investigate how the purely geometrical factors influence Zin, we measured Zin between 16 and 1,520 Hz in six dried dog lungs with the forced oscillation technique. In each of the lungs we found three resonances, at 36 +/- 5, 648 +/- 100, and 1,289 +/- 150 Hz, and at least two antiresonances (relative maxima in the real part of Zin), at 372 +/- 60 and 1,105 +/- 110 Hz. These data were fit with models featuring a detailed asymmetric branching network of the airways obtained from morphometric data published by Horsfield et al. (J. Appl. Physiol. 52: 21–26, 1982). On the basis of low-frequency (< 100 Hz) data alone, we first established a model of the acini, which was then attached to the end of the airway branching model. With a single scaling factor for the radius and length of the airways, the fit was unsatisfactory. Using sensitivity analysis techniques we determined which candidate variables of the structural model could influence Zin in a manner to improve the fit. We found that a two-parameter model accounting for separate central and peripheral airway diameter scaling provided a reasonable fit to Zin. On average the model required central diameter scaling close to unity (0.94 +/- 0.09), and the peripheral diameter scaling factor was 0.87 +/- 0.38. Over a range of parameter values that we believed were physiologically reasonable (i.e., scaling factors between 0.5 and 1.5), a single set of parameter values was found in all lungs. These results suggest that structurally based inverse models of Zin that include multiple antiresonances may provide information about airway geometry.

We compared the values of resistance produced by the forced oscillation technique (FOT) and the flow interruption technique (IT) when applied to six anesthetized paralyzed tracheostomized dogs. The FOT returned values of respiratory system resistance as a function of frequency [Re(f)] between 0.25 and 20 Hz. The IT returned a single value of resistance (Rinit) calculated by dividing the immediate change in tracheal pressure occurring upon interruption by the preinterruption flow. We found Rinit to coincide closely with Re(f) in the frequency range 5–20 Hz. Rinit has previously been interpreted as the high-frequency resistance of a resistance-elastance model of the respiratory system airways and tissues. It has also been shown previously, by direct measurement of alveolar pressure in dogs, that Rinit from the lungs alone is an accurate measure of airways resistance while Rinit obtained from the total respiratory system equals airways resistance plus a modest contribution from the chest wall. Re(f) at a frequency of approximately 10 Hz thus appears to be a useful quantity to measure as an index of airways resistance in the dog.

In 105 adults we investigated the influence of the body positions, sitting with respect to supine, on lung volumes and on the input resistance, (Rrs) and reactance (Xrs) of the respiratory system. Rrs and Xrs were measured between 2 and 26 Hz by means of a forced oscillation technique. Vital capacity (VC) and expiratory reserve volume (ERV) are smaller in the supine position; this reduction decreases with age and is less for ERV in male smokers than in nonsmokers. The Rrs values are larger in the supine position, and the slope of the Rrs-frequency curves tends to become less positive or negative, depending on sex, age, and smoking habits. Xrs decreases at lower frequencies. The changes in Rrs due to posture are larger in young smokers than in young nonsmokers. This is not explained by changes in ERV and may reflect changes in the intrinsic properties of the airways induced by smoking.

The respiratory impedances in healthy subjects and patients with advanced obstructive lung disease were measured between 2 and 32 Hz, using two forced oscillation techniques: the setup used previously by Grimby et al. (J. Clin. Invest. 47: 1455–1465, 1968) and a modified device in which the pneumotachograph is replaced by a 2-m-long tube and the ratio of pressures at both ends of the tube is determined. The advantages of the latter device are that 1) its impedance and frequency characteristics can be predicted by classical physics, 2) the only requirement for correct measurements are a match of the pressure transducers, and 3) high-pass filters are not needed to suppress the influence of breathing. On the other hand, the device is more sensitive to the turbulences induced by the subject's own breathing. This drawback can be avoided by interposing a piece of tubing between the mouth and proximal pressure recording site.

Using a forced oscillation technique, we measured the resistance (Rrs) and reactance (Xrs) of the respiratory system between 2 and 32 Hz at three different lung volumes in 15 healthy subjects and 7 patients with chronic obstructive pulmonary disease. Rrs and Xrs were partitioned, by means of a pressure recording in the esophagus, into the resistance and reactance of lung and airways (L) and the chest wall. The measurements were validated by checking the adequacy of the frequency response of the esophagus, by the lack of difference between thoracic and mouth flow, by an estimation of the error introduced by the shunt impedance of the cheeks, and by comparisons with the values of pulmonary compliance and resistance determined in the same subjects with classical techniques. In both healthy subjects and patients, the chest wall has a low resistance that increases somewhat at low lung volumes and behaves functionally as a two-compartment system, with low capacitance at frequencies exceeding 4 Hz. Rrs varies with lung volume and is markedly frequency dependent in patients; both phenomena are due primarily to corresponding variations of RL. In healthy subjects, at and above functional residual capacity (FRC) level, the lungs behave as a one-compartment system, the reactance of which is mainly determined by the gaseous inertance, at least beyond 2 Hz. In patients and in healthy subjects breathing below FRC, the observed frequency dependence of resistance and the simultaneous increase in resonant frequency can be simulated satisfactorily by Mead's two-compartment model, assuming a large increase in peripheral airways resistance.

We present a modification of forced oscillation technique for automated determination of total respiratory resistance during inspiration. The modifications consist of a computerized signal averaging and an optimization technique in the assessment of the resistance value. Thereby a favorable signal-to-noise ratio is obtained, allowing very low superimposed pressure oscillations. The method is validated by comparison with a conventional esophageal balloon method, by estimating added mechanical resistances in healthy subjects and by measuring the effect of bronchodilation in asthmatic children. The coefficient of variation as obtained from day-to-day measurements was about 7%. Mechanical resistances, estimated as the difference in total resistance with and without external resistance, were within 7% of their values determined for the resistances alone. A significant decrease in resistance was obtained in each of the asthmatic children following bronchodilation.

We have modified the measurements of the resistance of the respiratory system, Rrs, by the forced oscillation technique and we have developed equipment to automatically compute Rrs. Flow rate and mouth pressure are treated by selective averaging filters that remove the interference of the subject's respiratory flow on the imposed oscillations. The filtered mean Rrs represents a weighted ensemble average computer over both inspiration and expiration. This method avoids aberrant Rrs values, decreases the variability, and yields an unbiased mean Rrs. Rrs may be measured during slow or rapid spontaneous breathing, in normals and in obstructive patients, over a range of 3–9 Hz. A good reproducibility of Rrs at several days' interval was demonstrated. Frequency dependence of Rrs was found in patients with obstructive lung disease but not in healthy nonsmokers.

A technique is described allowing one to determine simultaneously the resistance and reactance of the total respiratory system for various frequencies. During spontaneous breathing, regularly recurring impulses are produced at the mouth by means of a loud speaker. A Fourier analysis of the mouth pressure and flow signals yields mean resistance and reactance values, over16 s, for all harmonics of 2 Hz up to 30 Hz. The values are in good agreement with those obtained in the absence of breathing and those determined by means of the forced oscillation technique and by body plethysmography. The reproducibility of the measurements is satisfactory (coefficient of variation: 11.6%).