Respiratory impedance measurements for assessment of lung mechanics: focus on asthma

This review discusses the history and current state of the art of the forced oscillation technique (FOT) to measure respiratory impedance. We focus on how the FOT and its interaction with models have emerged as a powerful method to extract out not only clinically relevant information, but also to advance insight on the mechanisms and structures responsible for human lung diseases, especially asthma. We will first provide a short history of FOT for basic clinical assessment either directly from the data or in concert with lumped element models to extract out specific effective properties. We then spend several sections on the more exciting recent advances of FOT to probe the relative importance of tissue versus airway changes in disease, the impact of the disease on heterogeneous lung function, and the relative importance of small airways via synthesis of FOT with imaging. Most recently, the FOT approach has been able to directly probe airway caliber in humans and the distinct airway properties of asthmatics that seem to be required for airway hyperresponsiveness. We introduce and discuss the mechanism and clinical implications of this approach, which may be substantial for treatment assessment. Finally, we highlight important future directions for the FOT, particularly its use to probe specific lung components (e.g., isolated airways, isolated airway smooth muscle, etc.) and relate such data to the whole lung. The intent is to substantially advance an integrated understanding of structure–function relationships in the lung.     

Lack of long-term effects of respiratory syncytial virus infection on airway function in mice

Epidemiological data suggests lower respiratory infections (LRI) with respiratory syncytial virus (RSV) are capable of causing long-term abnormalities in airway function. To directly test the effects of RSV LRI, we infected adult and weanling BALB/c mice with RSV (A2) or vehicle. Respiratory system impedance was used to assess baseline airway function and responses to iv methacholine (MCh) at 4, 8, 24 and 34 weeks post infection. In vitro airway responses were measured 24 weeks post infection using electrical field stimulation and MCh. Mice infected as adults showed no alterations in airway function. Mice infected as weanlings had increased MCh responses 24 weeks post infection. However, the increased response was not present 34 weeks post infection nor accompanied by alterations in in vitro responses or airway morphometry. This study did not detect long-lasting changes in airway function following RSV infection in mice. These data do not provide support for alterations in airway structure or function being responsible for the observed relationship between RSV infection in infants and asthma in later life.     

Assessment of upper airway mechanics during sleep

Obstructive sleep apnea, which is the most prevalent sleep breathing disorder, is characterized by recurrent episodes of upper airway collapse and reopening. However, the mechanical properties of the upper airway are not directly measured in routine polysomnography because only qualitative sensors (thermistors for flow and thoraco-abdominal bands for pressure) are used. This review focuses on two techniques that quantify upper airway obstruction during sleep. A Starling model of collapsible conduit allows us to interpret the mechanics of the upper airway by means of two parameters: the critical pressure (P_crit) and the upstream resistance (R_up). A simple technique to measure P_crit and R_up involves the application of different levels of continuous positive airway pressure (CPAP) during sleep. The forced oscillation technique is another non-invasive procedure for quantifying upper airway impedance during the breathing cycle in sleep studies. The latest developments in these two methods allow them to be easily applied on a routine basis in order to more fully characterize upper airway mechanics in patients with sleep breathing disorders.     

Guidelines for mechanical lung function measurements in psychophysiology

Studies in psychophysiology and behavioral medicine have uncovered associations among psychological processes, behavior, and lung function. However, methodological issues specific to the measurement of mechanical lung function have rarely been discussed. This report presents an overview of the physiology, techniques, and experimental methods of mechanical lung function measurements relevant to this research context. Techniques to measure lung volumes, airflow, airway resistance, respiratory resistance, and airflow perception are introduced and discussed. Confounding factors such as ventilation, medication, environmental factors, physical activity, and instructional and experimenter effects are outlined, and issues specific to children and clinical groups are discussed. Recommendations are presented to increase the degree of standardization in the research application and publication of mechanical lung function measurements in psychophysiology.     

Simulation of airway closure during forced vital capacity

Airway closure, which disconnects peripheral respiratory units from the trachea, has been observed during expiration to residual volume. It is attributed to dynamic compression that may cause unstable collapse and closure of small airways. During forced vital maneuvers, airway closure is expected to be more significant owing to the maximum expiratory effort. In the present study we have added a simulation of airway closure to the model developed by Elad and associates which simulated flow limitation during forced expiration. Progressive closure is simulated by variations in the number of branches and their cross-sectional areas rather than by change in tube law. The results demonstrate that peripheral airway closure may explain the reduction in maximal flow rate at small lung volumes. It can reproduce either the abrupt fall in maximal expiratory flow-volume curves as observed in dog lungs or the gradual decrease that has been observed in humans. This work was partially support by the Bat Sheva de Rothschild Foundation for Advancement of Science and Technology.     

无创通气下应用强迫振荡技术检测呼吸阻力

目的 构建强迫振荡测量系统,在无创正压通气(NPPV)条件下检测人呼吸系统阻抗(Rrs)和电抗(Xrs),用于评估肺阻力(RL)和弹件阻力(EL).方法 基于现有的强迫振荡技术,构建包括振荡发生器和信号分析软件在内的新强迫振荡测量系统,采用呼吸系统一阶线性力学模型(R-I-E模型)验证新系统测量的准确性和可靠性.8例健康正常人为研究对象,分别经鼻罩给予不同水平的双水平气道止压(BiPAP)和持续气道正压(CPAP)通气,探讨在不同通气模式和压力水平下利用Rrs无创评价R,的可行性.结果 (1)振荡压力和振荡流量的相干函数系数值r2=0.98,强迫振荡测量可靠.5 Hz强迫振荡测定的模型阻抗与模型的粘性阻力接近,两者平均相差(1.26±0.44)cm H2O·s·L-1,一敛性范嗣在(0.36～2.14)cm H2O·s·L-1.(2)8例在不同通气模式及压力条件下测定的Rrs值大小接近,与RL平均相差(0.16±1.58)cm H2O·s·L-1.RL的预计方程式为RL=1.40+0.77Rrs,[决定系数(r2)=0.43,P<0.01].(3)强迫振荡弹性阻力EFOT(EFOT=-2πfXrs)显著大于实际值EL,(P<0.01).两者存在低水平的相关(r=0.40,P<0.01).结论 新强迫振荡系统测量准确、可靠.Rrs近似地反映了RL的大小,RL预测值可用于优化NPPV的压力支持水平,使呼吸机提供的压力支持能有效地克服肺阻力.     

Comparisons of effects of intravenous and inhaled methacholine on airway physiology in a murine asthma model

Airway responses to intravenous (i.v.) and inhaled (i.h.) delivery of methacholine (MCh) in BALB/c and C57BL/6 mouse strains have been compared with and without ovalbumin (OVA)-induced airway inflammation. Bronchial reactivity to MCh was assessed in anaesthetised and tracheostomised animals by using an animal ventilator (flexiVent). We partitioned the response of the lungs into airway and parenchymal components in order to compare the contributions of the airways with those of the lung parenchyma to the pulmonary mechanical responses resulting from different routes of MCh administration. Our results indicate disparate physiological responses. Intravenous MCh delivery induced a higher maximum lung resistance than i.h. MCh in OVA-treated BALB/c mice but not in C57BL/6 mice. Inhaled MCh delivery led to a significantly larger fall in lung compliance and a greater impact on peripheral airways than i.v. MCh in both strains. In conclusion, i.v. and i.h. MCh produced disparate effects in different murine strains and variant responses in inflamed airways and healthy controls. The two methods of MCh delivery have important advantages but also certain limitations with regard to measuring airway reactivity in a murine model of allergic asthma.     

Impact of obesity on airway and lung parenchyma remodeling in experimental chronic allergic asthma

The impact of obesity on the inflammatory process has been described in asthma, however little is known about the influence of diet-induced obesity on lung remodeling. For this purpose, 56 recently weaned A/J mice were randomly divided into 2 groups. In the C group, mice were fed a standard chow diet, while OB animals received isocaloric high-fat diet to reach 1.5 of the mean body weight of C. After 12 weeks, each group was further randomized to be sensitized and challenged with ovalbumin (OVA) or saline. Twenty-four hours after the last challenge, collagen fiber content in airways and lung parenchyma, the volume proportion of smooth muscle-specific actin in alveolar ducts and terminal bronchiole, and the number of eosinophils in bronchoalveolar lavage fluid were higher in OB-OVA than C-OVA. In conclusion, diet-induced obesity enhanced lung remodeling resulting in higher airway responsiveness in the present experimental chronic allergic asthma.     

Acute effects of inspiratory pressure threshold loading upon airway resistance in people with asthma

Large inspiratory pressures may impart stretch to airway smooth muscle and modify the response to deep inspiration (DI) in asthmatics. Respiratory system resistance (Rrs) was assessed in response to 5 inspiratory manoeuvres using the forced oscillation technique: (a) single unloaded DI; (b) single DI at 25 cmH₂O; (c) single DI at 50% maximum inspiratory mouth pressure [MIP]; (d) 30 DIs at 50% MIP; and (e) 30 DIs at 50% MIP with maintenance of normocapnia. Rrs increased after the unloaded DI and the DI at 25 cmH₂O but not after a DI at 50% MIP (3.6 ± 1.6 hPa L s⁻¹ vs. 3.6 ± 1.5 hPa L s⁻¹; p = 0.95), 30 DIs at 50% MIP (3.9 ± 1.5 hPa L s⁻¹ vs. 4.2 ± 2.0 hPa L s⁻¹; p = 0.16) or 30 DIs at 50% MIP under normocapnic conditions (3.9 ± 1.5 hPa L s⁻¹ vs. 3.9 ± 1.5 hPa L s⁻¹; p = 0.55). Increases in Rrs in response to DI were attenuated after single and multiple loaded breaths at 50% MIP.     

Flow-induced oscillation of collapsed tubes and airway structures

The self-excited oscillation of airway structures and flexible tubes in response to flow is reviewed. The structures range from tiny airways deep in the lung causing wheezing at the end of a forced expiration, to the pursed lips of a brass musical instrument player. Other airway structures that vibrate include the vocal cords (and their avian equivalent, the syrinx) and the soft palate of a snorer. These biological cases are compared with experiments on and theories for the self-excited oscillation of flexible tubes conveying a flow on the laboratory bench, with particular reference to those observations dealing with the situation where the inertia of the tube wall is dominant. In each case an attempt is made to summarise the current state of understanding. Finally, some outstanding challenges are identified.     

Dynamic model of airway pressure drop

A multipath model of the mechanical behaviour of healthy lungs subject to a plethysmographic test (close to quiet breathing conditions) has been developed, which includes the main physiological nonlinearities. This model is built on a symmetric branching scheme based on Weibel's data, and uses non-linear fluid equations for the upper and lower airways. The alveolar gas compression, the changes in airway dimensions related to lung volume and/or transmural pressure, and the respiratory swings in glottic aperture have been taken into account. As clinically observed, the behaviour of the lungs, taken as a whole, seems linear, but it is confirmed by simulation that this linearity is only apparent. Simplifications and linearisations therefore need to be made carefully, only after their impact on the global behaviour of the lung is evaluated.     

Day-to-day variability of oscillatory impedance and spirometry in asthma and COPD

Variability in airway function may be a marker of disease activity in COPD and asthma. The aim was to determine the effects of repeatability and airway obstruction on day-to-day variability in respiratory system resistance (Rrs) and reactance (Xrs) measured by forced oscillation technique (FOT). Three groups of 10 subjects; normals, stable asthmatic and stable COPD subjects underwent daily FOT recordings for 7 days. Mean total and inspiratory Rrs and Xrs, and expiratory flow limitation (EFL) Index (inspiratory – expiratory Xrs), were calculated. The ICC's were high for all parameters in all groups. Repeatability, in terms of absolute units, correlated with airway obstruction and was therefore lowest in COPD. Day-to-day variability was due mostly to repeatability, with a small contribution from the mean value for some parameters. FOT measures are highly repeatable in health, stable asthma and COPD in relation to the wide range of measures between subjects. For home monitoring in asthma and COPD, either the coefficient of variation or individualized SDs could be used to define day-to-day variability.     

The contribution of the pulmonary microvascular pressure in the maintenance of an open lung during mechanical ventilation

Changes in pulmonary hemodynamics modify the mechanical properties of the lungs. The effects of alterations in pulmonary capillary pressure (Pc) were investigated on the airway and lung tissue mechanics during positive-pressure ventilation and following lung recruitment maneuvers. Isolated, mechanically normoventilated (PEEP 2.5 cmH(2)O) rat lungs were perfused with Pc set to 0 (unperfused), 5, 10 or 15 mmHg, in random sequence. The pulmonary input impedance (ZL) was measured at end-expiration before and after a 10-min long ventilation. After inflation of the lung to 30 cmH(2)O during P-V curve recordings, another set of ZL was measured to evaluate the degree of recruitment. The PEEP was then decreased to 0.5 cmH(2)O and the sequence was repeated. Airway resistance and parenchymal damping and elastance (H) were estimated from ZL by model fitting. From the P-V curves, elastance (E) and hysteresis indices were determined. Mechanical ventilation at both PEEP levels resulted primarily in elevations in the tissue parameters, with the greatest increases at the 0 Pc level (H changes of 27.8+/-4.2 and 61.3+/-3.7% at 2.5 and 0.5 cmH(2)O PEEP, respectively). The maintenance of physiological Pc (10 mmHg) led to a significantly lower elevation in H (11.6+/-1.5% versus 31.4+/-3.6%). The changes in the oscillatory mechanics were also reflected in E and the hysteresis of the P-V curves. These findings indicate that pulmonary hypoperfusion during mechanical ventilation forecasts a parenchymal mechanical deterioration. Physiological pressure in the pulmonary capillaries is therefore an important mechanical factor promoting maintenance of the stability of the alveolar architecture during positive-pressure mechanical ventilation.     

The i.v. infusion of mannitol decreases airway responsiveness to methacholine in asthma

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway inflammation and oedema. The oedema of the airway wall may contribute to airway narrowing and hyperresponsiveness by increasing airway wall thickness, by altering airway compliance, or by impairing the transmission of the lung elastic recoil to the airway smooth muscle (ASM). We hypothesized that the i.v. infusion of mannitol, an osmotic diuretic, would reduce the water content of the airway wall in asthma and COPD, thus decreasing airway responsiveness to methacholine (MCh). In eight asthmatic and in six COPD patients, airway responsiveness to MCh, lung volumes and lung mechanics were measured before and after infusion of mannitol. In the asthmatics, mannitol decreased airway responsiveness to MCh and lung elastic recoil. In the COPD patients, no differences were recorded after mannitol infusion. These data suggest that the airway wall oedema, in asthma, has an impact on airway responsiveness to MCh. The differential effect of mannitol in asthma versus COPD, may relate to the specific pathologic features of the diseases.     

Emotions and airway resistance in asthma: study with whole body plethysmography

The role of emotions as potential triggers of asthmatic airway obstructions was examined by whole body plethysmography. Three affectively homogeneous picture series (IAPS) were presented with video glasses to induce pleasant, unpleasant, and neutral emotional states in 32 asthmatic and 32 nonasthmatic participants while they were seated in a Jaeger Bodytest plethysmograph. Airway resistance, specific airway resistance, thoracic gas volume, and mood were measured immediately after each presentation, in addition to specific airway resistance before and during each presentation. Airway resistance and specific airway resistance were significantly increased after and during pleasant and unpleasant stimulation compared to neutral stimulation in asthmatic patients and also, but less pronounced, in nonasthmatic controls. The results show that the experience of pleasant and unpleasant emotions can provoke increased airway resistance especially in asthmatic patients.     

Convergence properties of a new technique for estimating parameters in a nonlinear viscoelastic lung model in newborns

The aim of this study was to develop a new technique to estimate parameters (airway resistance, inertance, tissue damping, and elastance; RIGH) of a viscoelastic lung model. The nonlinear RIGH-model was linearized by re-parametrization (model linearization, ML), and the parameters were calculated by one-dimensional line search of least-squares estimations. The convergence properties, the number of iterations, and computing time were compared between different search algorithms using the frequency responses of small animals and infants without and with added noise. While all of the algorithms converged in case of undisturbed frequency responses, only two algorithms converged in case of noise. ML provided always the lowest number of iterations and the shortest computing times. ML allows for reliable and accurate parameter estimation of the RIGH model.     

An adaptive analogue tracker for automatic measurement of lung parameters

This paper describes the design and results obtained using simple electronic circuits specially designed for implementing a simple lung-parameter tracking algorithm for identification of the mechanical properties of the lung. Unlike the commonly used loop-flattening technique, the adaptive electronic tracker is able to monitor continuously the mechanical properties of the respiratory sysem. It is capable of tracking the rapid changes in lung parameters as the frequency of breathing changes. The design of the adaptive tracker is based on equation-error formulation and the global asymptotic stability of the adaptive tracking equations is guaranteed. The cheapness and simplicity of the tracker makes it suitable for clinical applications.     

Flecainide blocks the stimulatory effect of veratridine on slowly adapting pulmonary stretch receptors in anaesthetized rabbits without changing lung mechanics

We examined the responses of slowly adapting pulmonary stretch receptors (PSRs), total lung resistance (R_L) and dynamic lung compliance (C_dyn) to administered veratridine before and after pretreatment with atropine or flecainide in anaesthetized, artificially ventilated rabbits with bilateral vagotomy. Administration of veratridine (10 and 30 μg kg^-1) caused vigorous stimulation of PSRs, resulting in a tonic discharge of receptors during both inflation and deflation, but did not significantly alter either R_L or C_dyn. The veratridine-induced PSR stimulation became more prominent, as the dose of this alkaloid was increased. Pretreatment with atropine (1 or 2 mg kg^-1) had no significant effect on the excitatory response of PSRs to veratridine. The veratridine induced PSR stimulation was inhibited by treatment with flecainide (1, 2 and 3 mg kg^-1), a sodium channel blocker, and this inhibition was dose-dependent. These results suggest that activation of PSRs following veratridine administration probably related to the increased influx of sodium ions into the receptive terminals but does not depend upon bronchoconstriction.     

外源性H2S干预对O3致哮喘小鼠气道反应性和气道重塑的影响

 目的: 探讨外源性硫化氢(hydrogen sulfide,H₂S)对臭氧(ozone,O₃)致哮喘小鼠气道反应性和气道重塑的影响。方法: 将15只SPF级C57BL/6雌性小鼠随机分为对照组、O₃组和NaHS+O₃组,每组5只。O₃处理前0.5 h,对照组和O₃组腹腔注射生理盐水,NaHS+O₃组腹腔注射NaHS(H₂S的供体);O₃组和NaHS+O₃组隔天用O₃处理,对照组则呼吸清洁空气。持续4周后无创测定小鼠的气道反应性,随后进行气管环张力测定,通过肺组织HE染色测定支气管基底膜周径(Pbm)和管壁总面积(Wat)并标准化衡量气道重塑程度,并行AB-PAS染色测定肺组织中杯状上皮细胞的变化情况以进一步评价气道重塑程度。结果: 与对照组相比,O₃组小鼠的气道反应性显著增高;NaHS+O₃组明显低于O₃组,但与对照组相比差异无统计学显著性。与对照组相比,O₃组小鼠在乙酰甲胆碱刺激时的气管收缩力显著加大;NaHS+O₃组明显小于O₃组。与对照组相比,O₃组小鼠的支气管壁厚度明显加大;NaHS+O₃组显著小于O₃组但仍大于对照组。与对照组相比,O₃组小鼠肺组织中杯状上皮细胞占气道上皮细胞总面积的百分比显著上升;NaHS+O₃组显著低于O₃组但仍高于对照组。结论: 外源性H₂S对O₃所致哮喘的气道高反应性和气道重塑有缓解与保护作用,有望为临床药物治疗哮喘提供新靶点。