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

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Abstract

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.

Introduction

The concept of measuring mechanical impedance to probe mechanical lung function has been around for nearly three quarters of a century. The concept is driven by the general notion that in order to breathe, a pressure difference needs to be created across the lungs causing some resulting airflow and subsequent distribution of that air to gas exchanging regions of the lung. Since breathing is oscillatory, it seems reasonable to ask which mechanical properties govern the relation between oscillatory pressure and flow, particularly as they impact the capacity to sustain lung function. The original studies simply measured transpulmonary pressure and airflow during breathing and calculated a resultant parameter to capture the in-phase (or energy loss) aspect of this relation, called lung resistance (RL), and the out-of-phase (or energy storage component), which they called lung compliance (CL, or lung elastance EL which is the inverse of compliance) (Otis et al., 1950, Mead and Whittenberger, 1954). These “effective” properties reflect the combined influence of a plethora of specific structures ranging from airway diameters, airway walls, parenchymal tissue, and the relative distribution of all these in a rather complex and asymmetric anatomy. Indeed, Otis et al. (1950) elegantly pointed out that, if the lung was diseased in a heterogeneous fashion, these properties would behave in a distinct fashion relative to a healthy lung when probed as a function of frequency. By implication, measurement of these properties versus frequency should reflect not only the degree but the pattern of a disease. Moreover, since the heterogeneity was most likely arising from the smaller airways or lung periphery, these data might be sensitive to such structures.

In parallel with these insights, Dubois et al. (1956) fathered the forced oscillation technique (FOT). Intrigued by the potential to probe not only overall mechanics, but measures sensitive to disease severity and distribution, he proposed using forced flow oscillations applied over a range of frequencies all at once, measuring the necessary flow and pressures simultaneously and then calculating the R and E at each frequency. In actuality, he measured what was termed impedance (Z), which is a complex term with a real (in-phase) and imaginary (out-of-phase) component of the pressure-flow relation calculated at each excitation frequency. From these real and imaginary parts, one can simply calculate the effective R and E. In order to avoid the need for an esophageal balloon, he applied the forcing externally (rather than by the subject breathing) and at frequencies that did not interfere with the subject breathing. Thus, he measured respiratory system impedance (Zrs) rather than lung impedance (ZL).

This review discusses the history and current state of the art of the forced oscillation technique to measure respiratory impedance. It follows several other reviews (Lutchen and Suki, 1996, Bates and Lutchen, 2005). Similar to these reviews, 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. We cover the history of respiratory impedance measurements and advancements to provide physiological relevance to the measurements as well as to directly probe airway caliber with the FOT. We also present recent uses of the FOT in research and clinical applications, as well as future directions for the FOT. The intent is to utilize respiratory impedance measurements from the FOT to substantially advance an integrated understanding of structure–function relationships in the lung.

Section snippets

History of respiratory impedance measurements

The first study formalizing the FOT proposed two methods (Dubois et al., 1956) (Fig. 1). In the first method, pressure oscillations are created around the chest wall (Pcw) by oscillating the air surrounding the subject in an enclosed head-out chamber. The resulting flow oscillations that occur at the airway opening (Qao) are measured. The ratio Pcw/Qao is called transfer impedance (Ztr). Alternatively, one can oscillate flows directly into the mouth and measure the trans-respiratory pressures

FOT for frequencies surrounding breathing

By the early 1990s, it became increasingly clear that gleaning sensitive and specific physiological insight in health and disease is more likely if the FOT could be applied to lower frequencies that span typical breathing rates. A hint of this arose when Hantos et al. (1986) showed respiratory input impedance data from 0.1 to 4 Hz in healthy subjects using a complicated speaker system and protocol (the subject had to hold their breath with the glottis open for about 20–25 s while the oscillations

Tracking airway caliber in real-time using single frequency FOT

Up until recently, the FOT has been primarily used to study the frequency dependence of both lung resistance and lung elastance at a given moment in time. The FOT can be modified, however, to address sensitive and important changes in lung mechanics that may occur during specific breathing maneuvers. While the concept of using the FOT with a single frequency excitation was introduced early on (Nadel and Tierney, 1961), it has not been exploited until recently. By using a time analysis of the

Clinical applications of the FOT—single and multiple frequencies

With the maturation of the FOT as a research tool, it has also gained increased potential for clinical applications. While spirometry has become ubiquitous for assessing lung function, it has its limitations. Spirometry is dependent on patient cooperation to provide consistent vigorous forced breathing maneuvers. Also, while indices derived from spirometry are well calibrated for normative data by age, height, etc., they do not readily nor explicitly reflect specific lung structures or regions.

Future directions to develop an integrated understanding of structure–function relationships in lung diseases

It is fair to assume that, for human asthma, the constituent changes in each of the structures comprising a lung (e.g., ASM cells, ASM bundles, airway walls, and the entire airway tree) will eventually manifest themselves in whole lung FOT measurements taken across specific frequency ranges and/or at a particular frequency while performing particular breathing maneuvers such as a DI. Since the FOT is inherently a global functional measurement, it is complex to distill from whole organ FOT alone

Summary and conclusions

Most lung diseases are a manifestation of a complex set of processes that alter distinctive structural components in the lung so as to eventually degrade lung function. Historically, the FOT was proposed as a potential easy and inexpensive means to assess function with minimal patient cooperation. After all, the FOT explicitly measures effective mechanical properties associated with the degree of energy dissipation (R) and energy storage (E) associated with oscillating at a given frequency. For

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