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The mechanisms for the generation of breathlessness are complex and multifactorial. The respiratory centres in the brainstem control respiratory muscle activity through respiratory neural drive to regulate chest wall expansion, lung inflation, and ventilation. Neural

respiratory drive increases if:

1. Respiratory muscles experience increased loading and/or there is a reduction in their force generating capacity

2. There is increased ventilatory demand (119).

Breathing is usually automatic, however, is also under volitional control through higher cortical motor centres. Afferent feedback is provided by central and peripheral chemoreceptors, mechanoreceptors, and sensory receptors directly to both the automatic respiratory centres in the brainstem and volitional higher cortical motor centres. It is believed that a copy of the efferent neural signals that arise from the motor cortex or respiratory centres of the brainstem to the respiratory muscles is also sent as “central corollary discharge” to sensory areas of the brain cortex (119, 245). The intensity of perceived breathlessness therefore relates to the awareness of the need to increase respiratory neural drive. Qualitative distinct sensations of breathlessness (such as chest tightness) and the unpleasantness of breathlessness (such as air hunger), which are different from the intensity of breathlessness are more complex and relate to the integration of distinct afferent sources (119, 245).

Functional neuroimaging studies suggest that the neural structures involved in the perception or generation of the sensation of breathlessness include the insular cortex, prefrontal cortex, anterior and posterior cingulate cortices, cerebellum, amygdala, striatum and periaqueductal grey matter (119, 245). Thus many of the same neural structures that are involved in the perception of pain, seem to also be involved in the perception of breathlessness, which may contribute to the discomfort and distress associated with an increased sensation of ventilation. Notably some of these neural structures such as the insular cortex and amygdala are also important structures involved in the processing of

emotion, self-awareness, arousal, consciousness, decision making, suffering, memory and motivation (119, 245).

In COPD there are multiple physiological mechanisms that lead to breathlessness including increased resistive load from airway narrowing and increased elastic load from hyperinflation resulting in impaired ventilatory mechanics. Hypoxia and/or hypercapnoea may be also present, leading to stimulation of chemoreceptors, and dynamic airway compression may stimulate receptors within the airway (1, 2, 245).

Static and dynamic hyperinflation

In COPD the combined effects of permanent parenchymal destruction (emphysema) and airway dysfunction causing increased airway resistance (from small airway inflammation and altered airway smooth muscle tone) lead to expiratory airflow limitation. Emphysema causes reduced lung elastic recoil pressure, which leads to a reduced driving pressure for expiratory flow through narrowed and poorly supported airways in which airflow resistance is significantly increased. When expiratory airflow limitation is present, expiratory flow rates are independent of expiratory muscle effort and are instead determined by the static lung recoil pressure and the resistance of the airways upstream from the flow-limiting segment (1).

In healthy lungs, the balance between the opposing forces generated by inward elastic recoil pressure of the lung and the outward recoil pressure of the chest wall determine the relaxation volume of the respiratory system. By contrast, in COPD emphysema leads to increased lung compliance (i.e. reduced inward lung elastic recoil pressure), therefore there is less counterbalance to the outward recoil pressure of the chest wall (119, 245). To empty the lungs during expiration to the normal resting lung volume therefore requires more time,

however the expiratory time available is insufficient because it is automatically interrupted by the next inspiration. This leads to an increased volume of air remaining in the lungs at the end of expiration, also termed air trapping or ‘‘static’’ lung hyperinflation, which in turn leads to reduced inspiratory capacity. The development of static lung hyperinflation in patients with COPD is an insidious process that occurs over decades, with residual volume increasing first (due to increased airways closure), followed by end-expiratory lung volume (due to airflow limitation and altered static mechanics), and finally total lung capacity increases as lung compliance increases (119, 245).

Importantly, however, the volume of air remaining in the lungs at the end of expiration in COPD is not static, but dynamic, being dependent on expiratory time and tidal volume. Dynamic hyperinflation (DH) refers to the increase in end-expiratory lung volume that occurs in patients with airflow limitation when minute ventilation increases, such as during exercise, with acute exacerbations, when hypoxia occurs, or with anxiety. Importantly DH negatively affects chest wall geometry and mechanics, so that inspiratory muscles operate at a shorter, less effective sarcomere length. This mechanical disadvantage adds a restrictive defect to the underlying obstructive mechanical defect (119, 245).

DH often occurs in patients with moderate to severe COPD and significantly contributes to both breathlessness and exercise intolerance because the ability to increase ventilation when the demand arises is greatly limited. During exercise DH leads to many adverse effects including:

• sudden increases in inspiratory muscles loads, which increase the work and oxygen cost of breathing

fibres in the diaphragm

• reduced ability to increase the tidal volume appropriately during exercise (due to reduced inspiratory capacity from hyperinflation) leading to early mechanical limitation of ventilation

• mechanically constrained tidal volume expansion, together with high fixed physiological dead space, leads to carbon dioxide retention and arterial oxygen desaturation during exercise

• negative effects on dynamic cardiac function (119, 245).

Each of these physiological effects contributes to breathlessness and exercise limitation. Notably, as ventilatory drive increases (for example if a person with moderate COPD begins to walk uphill), the resulting increase in ventilation produces further DH. Thus the only way to increase minute ventilation is to increase the respiratory rate, which comes at the cost of greater dead space ventilation and decreased dynamic compliance. In the end the person cannot match ventilation to respiratory drive, leading to cessation of exercise and breathlessness (119, 245).

DH also contributes to high intensity breathlessness during other periods of increased ventilation in flow-limited patients with COPD, such as during an exacerbation or an episode of anxiety. During exacerbations of COPD, airflow limitation increases (which in turn increases the time required during expiration to adequately empty the lungs) and both ventilatory demand and respiratory rate increase (due to increased ventilation/perfusion mismatch). These physiological effects lead to acute DH, which contributes to worsening breathlessness (119, 245).

predicted value, as measured using body plethysmography, or if either residual volume (RV) or RV/TLC are above the upper limits of normal (1). Strategies that can specifically address hyperinflation (including pulmonary rehabilitation, endobronchial valve insertion and lung volume reduction surgery) were discussed in section 1.2.15. Other breathlessness management strategies (such as breathing techniques) that are helpful for patients with dynamic hyperinflation will be discussed in section 1.5.1.6.