The respiratory muscles

Respiratory disease

The primary symptom and exercise-limiting factor in respiratory disease is dyspnoea. In this section the impact of respiratory disease upon respiratory mechanics, respiratory muscle function and ventilatory demand will be described. Readers wishing to know more about the physiological basis of respiratory disease are referred to Hamid and colleagues’ comprehensive text on the subject (Hamid et al, 2005).

Chronic heart failure and pulmonary hypertension

Patients with chronic heart failure (CHF) present with dyspnoea, exercise intolerance and fatigue. Chronic heart failure is a complex condition that generates a number of interrelated pathophysiological changes that affect skeletal muscle, the vasculature, neurohormonal systems and the lungs (Brubaker, 1997).

Inspiratory muscle dysfunction has not been assessed as widely or with the same rigour in CHF as in COPD. For example, there are no biopsy studies of diaphragm composition, and only one study has examined diaphragm twitch pressure (Hughes et al, 1999). Notwithstanding this, the evidence of inspiratory muscle weakness is consistent and compelling (Ribeiro et al, 2009). It has been suggested that inspiratory muscle weakness may be part of the generalized atrophy that is common in CHF, but there is some evidence that there may be selective weakness of the inspiratory muscles (Ribeiro et al, 2009). Indeed, inspiratory muscle strength has been shown to have prognostic value (Frankenstein et al, 2008, 2009), which underscores its importance. Furthermore, inspiratory muscle weakness is correlated with a number of indices of haemodynamic dysfunction, including cardiac output and the severity of pulmonary hypertension (Filusch et al, 2011).

Patients with CHF tend to adopt a rapid, shallow and constrained breathing pattern during exercise (Johnson et al, 2000). This appears to be an adaptive response to changes in the demand / capacity relationship of the inspiratory muscles. Lung compliance is reduced by pulmonary oedema and pulmonary fibrosis (Wright et al, 1990), which increases the work of breathing (Cross et al, 2012). An interesting feature of the rapid, shallow breathing pattern is that it coexists with expiratory flow limitation and a reduction in end-expiratory lung volume. The result is an increase in both the elastic and resistive work of breathing, the latter being present during both phases of respiration, whilst the former is seen only during inspiration (Cross et al, 2012). Unlike patients with COPD and asthma, patients with CHF do not hyperinflate in order to decrease their expiratory flow limitation (Johnson et al, 2000). Instead, unpleasant breathing sensations are minimized by adopting a rapid, shallow breathing pattern. This strategy suggests that the sensations associated with hyperinflation are more unpleasant than those associated with expiratory flow limitation and rapid, shallow breathing. This is entirely reasonable, given that hyperinflation in the presence of pulmonary oedema and fibrosis would increase inspiratory elastic work considerably (Cross et al, 2012). The mechanisms underlying the greater resistive work of breathing in CHF are uncertain, but may be related to worsening of pulmonary congestions and / or bronchoconstriction during exercise (Cross et al, 2012).

There are also a number of abnormalities that increase the ventilatory requirement of exercise in CHF, and thus increase the demands imposed upon the respiratory muscles. For example, diffusion impairment is present in 67% of patients with severe CHF (Wright et al, 1990). This may be due to pulmonary fibrosis, but may also be due to the influence of an impaired cardiac output upon ventilation/perfusion mismatching (Lewis et al, 1996), which elevates the physiological dead space. Furthermore, rapid, shallow breathing increases dead space ventilation further, because it generates a higher than normal ratio of dead space to tidal volume (V_D / V_T). Higher dead space necessitates an increase in _E in order to minimize changes in blood gases. A further corollary of rapid, shallow breathing is that the higher inspiratory flow rate increases the relative functional demands upon the inspiratory muscles, which must operate on a weaker part of their force–velocity relationship (see Ch. 4, Fig. 4.1).

Elevated peripheral chemoreflex sensitivity is found in as many as 40% of patients with CHF, and may contribute to the exaggerated exercise hyperpnoea, as well as sympathoexcitation (Chua et al, 1997). Recently, it was found that peripheral chemoreflex sensitivity to carbon dioxide is significantly higher in patients with CHF who have inspiratory muscle weakness than in those who do not (Callegaro et al, 2010). The study authors hypothesized that the elevated chemoreflex sensitivity was secondary to the sympathoexcitation resulting from metaboreflex activation in weakened / fatigued inspiratory muscles. This is consistent with the finding that ventilatory and cardiovascular responses to locomotor muscle metaboreflex activation are increased in patients with CHF (Piepoli et al, 1996). Thus, exaggerated responses to chemoreflex and metaboreflex stimulation during exercise most likely conspire to exacerbate an already elevated ventilatory demand.

For reasons that are not yet fully understood, MIP is an independent risk factor for myocardial infarction and cardiovascular disease death (van der Palen et al, 2004). One study has also shown that patient survival was lower in those patients with low MIP (Meyer et al, 2000).

Finally, pulmonary arterial hypertension (PAH) is worthy of mention at this point; the condition is associated with heart failure, but may also be idiopathic. The symptomatology and respiratory manifestations of PAH are similar to those of CHF, including respiratory muscle weakness (Meyer et al, 2005). Furthermore, there is evidence that inspiratory muscle strength may influence exercise tolerance in patients with PAH (Kabitz et al, 2008a).

Thus patients with CHF and / or PAH have an increased demand for inspiratory muscle work and a reduced capacity to supply this demand due to muscle dysfunction. In the section ‘Respiratory muscle involvement in exercise limitation’ the implications of this in the context of respiratory muscle-induced limitations to exercise tolerance will be considered, and Chapter 4 will review the evidence supporting specific respiratory muscle training for patients with CHF.

Neurological and neuromuscular disease

Neurological and neuromuscular diseases include conditions that affect the brain, spinal cord, nerves and muscles. Impairment can be the result of intrinsic muscle dysfunction, or arise indirectly via neurological / nerve dysfunction. The functional consequences are broadly divided into spasticity and paralysis. For simplicity, these conditions are considered collectively in this section under the terminology of neuromuscular disease (NMD), beginning with spinal cord injury.

Obesity

The influence of obesity upon respiratory muscle function stems primarily from the mechanical impedances imposed by fat deposition upon the movement of the chest wall and diaphragm (Salome et al, 2010). Fat deposited on the chest wall decreases respiratory system compliance, creating a restrictive pulmonary defect. Fat deposited within the abdominal cavity reduces its compliance and impedes diaphragm movement into the abdominal compartment. Respiratory system compliance of obese people is approximately half that of lean people, and reduces still further in obese people when supine (Naimark & Cherniack, 1960).

The effect of obesity upon lung volumes is primarily to reduce functional residual capacity (FRC) and end-expiratory lung volumes (EELV) (Babb et al, 2008b), owing to increased respiratory system recoil. This increases the likelihood of expiratory flow limitation (Ferretti et al, 2001). In addition, when breathing closer to residual volume, airway calibre is smaller and thus airway resistance is greater. For example, compared with overweight people (BMI 27 kg·m^− 2), airway resistance was 56% greater in obese people (body mass index [BMI] 46 kg·m^− 2); airway resistance was also correlated with the reduction in FRC (Zerah et al, 1993). Total lung capacity and residual volume tend to be preserved, but inspiratory reserve volume tends to increase and expiratory reserve volume to decrease (due to the reduction in EELV). However, in extreme obesity TLC may be impaired by the inability of the inspiratory muscles to overcome the increased compliance of the chest wall and abdominal compartment, or by a reduction in thoracic volume due to ingress of adipose tissue (Salome et al, 2010). Overall, the effects of obesity are to roughly double the work of breathing (Naimark & Cherniack, 1960; Pelosi et al, 1996; Kress et al, 1999), with most of the increase deriving from the increased elastic work (Pelosi et al, 1996).

The relative overloading of the respiratory pump in obesity is also reflected in a reduced maximum voluntary ventilation (MVV), the decline being greater with higher BMIs. However, this decline in MVV is greater than the declines in FEV₁ and FVC would predict (Weiner et al, 1998), which points strongly to a deficit in the function of the inspiratory muscles. Airway function is impaired slightly, with FEV₁ and FVC tending to decrease with increasing BMI (Salome et al, 2010). Since both indices decrease to the same extent, the impairment in FEV₁ is most likely secondary to the decrease in FVC, and not to a direct effect of obesity upon airway diameter (Salome et al, 2010). Changes in breathing mechanics mean that obesity leads to a reduction in EELV during exercise, with the consequence that some expiratory flow limitation may result (Rubinstein et al, 1990).

The effect of obesity upon the ventilatory requirement for exercise is self-evident, but the combination of an elevated oxygen and ventilatory cost of locomotion is exacerbated by poor aerobic fitness due to deconditioning. The latter leads to an early ventilatory compensation for metabolic acidosis. An important adaptive response during exercise is the adoption of a rapid and shallow breathing pattern, which increases the relative functional demands upon the inspiratory muscles, as well as the ventilatory requirement per se (by increasing the ratio of dead space ventilation to tidal volume). These factors conspire to create a huge increase in the requirement for respiratory muscle work to meet the elevated ventilatory requirement.

Respiratory muscle strength and endurance appear to be well preserved in some obese adults (Yap et al, 1995; Weiner et al, 1998; Collet et al, 2007), but studies have reported a small (~ 10%) impairment of respiratory muscle strength and endurance (Weiner et al, 1998; Chlif et al, 2005). Interestingly, even in those with relatively well-preserved respiratory muscle function, weight loss following bariatric surgery improves inspiratory and expiratory muscle strength by around 20% (Weiner et al, 1998). One thing is clear: inspiratory muscle function is inversely related to BMI. A significant negative correlation has been observed by some investigators (Chlif et al, 2005), whilst others have noted that inspiratory muscle strength was slightly lower (~ 15%) in patients with a BMI > 49 kg·m^− 2 than in those with a BMI < 49 kg·m^− 2 (Collet et al, 2007).

Dyspnoea is a common complaint amongst obese individuals, both at rest and during exercise. This may be in part due to inspiratory muscle weakness (Chlif et al, 2007, 2009), but alterations in respiratory system mechanics also contribute. Breathing is associated with a rapid, shallow pattern, an increased ventilatory drive to the inspiratory muscles and an increased inspiratory muscle work (Chlif et al, 2007; Chlif et al, 2009). An increased oxygen cost of breathing has been implicated specifically in the dyspnoea associated with obesity (Babb et al, 2008a).

Another important factor to be borne in mind with regards to the influence of obesity upon breathing is the existence of co-morbidities. For example, it is increasingly common for obesity to be present with COPD (Franssen et al, 2008). There is also a well-established causal relationship between obesity and obstructive sleep apnoea (Schwartz et al, 2010), as well as hypoventilation syndrome (Anthony, 2008). Less well established, but an area of growing interest, is the apparent association between obesity and asthma, with some researchers suggesting that there may be a causal relationship between the two conditions (Sood, 2005), in which obesity is the antecedent (Ford, 2005). A putative underlying mechanism for the development of asthma, as well as the exacerbation of existing disease, is the production of pro-inflammatory cytokines by adipose tissue (Sood, 2010).

Thus, obese patients have an increased demand for inspiratory muscle work, which arises from complex changes in respiratory system mechanics. Furthermore, in those with inspiratory muscle weakness there is also a reduced capacity to supply this elevated demand. In the section ‘Respiratory muscle involvement in exercise limitation’, respiratory muscle-induced limitations to exercise tolerance will be considered, and Chapter 4 will review the evidence supporting specific respiratory muscle training for obese people.

Ageing

The process of normal ageing is associated with a number of changes that affect breathing (Janssens et al, 1999). Thus deterioration in pulmonary mechanics, lung function, locomotor efficiency and respiratory muscle function, as well as remodelling of pulmonary vasculature, all impact upon the demand / capacity relationship of the respiratory muscles.

The senescent changes to the pulmonary system have been dubbed ‘senile emphysema’ (Janssens et al, 1999) and are present from the age of 50 years, becoming most apparent at around 80 years (Britto et al, 2009). The most important of these changes are a decrease in the static recoil of the lung, a decrease in chest wall compliance and a reduction in the strength of the respiratory muscles (Janssens et al, 1999). Accordingly, many of the factors that increase the demand for inspiratory muscle pressure generation in COPD are also common to normal ageing. These include dynamic hyperinflation (Deruelle et al, 2008), and an increase in mechanical ventilatory constraints during exercise (DeLorey & Babb, 1999). Older people also adopt a rapid, shallow breathing pattern, and exhibit a greater dead space to tidal volume ratio (V_D / V_T), which necessitates an increase in _E (DeLorey & Babb, 1999). There is also remodelling of the pulmonary vasculature, leading to increased vascular stiffness, resistance and pressure (Taylor & Johnson, 2010). These changes reduce pulmonary capillary blood volume and increase heterogeneity in the distribution of ventilation and perfusion. The resultant reduction in membrane diffusing capacity is consistent with a reduction in alveolar–capillary surface area (Taylor & Johnson, 2010). These changes make a small additional contribution to the ventilatory demand. In addition, the mechanical efficiency of exercise appears to be lower in older people (McConnell & Davies, 1992).

The term sarcopenia first appeared in the literature in the early 1990s to describe the age-related loss of muscle mass (Rogers & Evans, 1993). Respiratory muscles are also affected by this process, and their strength is correspondingly lower in older people (McConnell & Copestake, 1999); indeed, respiratory muscle strength is strongly and independently correlated with hand grip strength (Enright et al, 1994). Furthermore, respiratory muscle strength is also independently related to decline in mobility in older people (Buchman et al, 2008).

Finally, the influence of co-morbidities must also be borne in mind, since the majority of older people are not without disease. Accordingly, the age-related changes described above serve to exacerbate disease-related impairments. The picture in older people is therefore one of an emerging load / capacity imbalance within the respiratory muscles that worsens progressively with advancing age, and is exacerbated by chronic disease. In the section ‘Respiratory muscle involvement in exercise limitation’, the implications of these changes for exercise tolerance will be considered, and Chapter 4 will review the evidence supporting specific respiratory muscle training for older people.

Miscellaneous conditions

There are a number of other conditions that are associated with primary and functional respiratory muscle dysfunction, and / or imbalance of the demand / capacity relationship. These conditions have been less well studied from a respiratory perspective than those in the previous section, but are nevertheless worthy of consideration since specific training of the respiratory muscles could be considered as part of the management of these conditions. At best, functional weakness of the respiratory muscles impairs patients’ exercise tolerance; at worst, it can lead to life-threatening events or complications.

The underlying cause of respiratory muscle weakness in the conditions described below is diverse, ranging from the existence of a ‘myopathic muscle milieu’ (e.g., corticosteroid treatment), to profound disuse (mechanical ventilation). Where applicable, the evidence supporting the application of specific respiratory muscle training to these conditions will be described in Chapter 4.

Healthy people

In healthy young people, the physical work undertaken by the respiratory muscles during the task of pumping air in and out of the lungs can be immense (Harms & Dempsey, 1999), but even in non-athletes the work of breathing has been shown to influence exercise tolerance. Research suggests that this occurs via two mechanisms: (1) by contributing to perceived effort, and (2) by exacerbating the demands placed upon the circulatory system for blood flow. This section will consider how these factors contribute to exercise limitation, with an emphasis on the role and repercussions of respiratory muscle work.

An important premise in the argument that respiratory muscles limit exercise performance in healthy people is that the muscles operate at, or close to, the limits of their capacity. When muscles work in this way, they become fatigued (see Ch. 1, ‘Mechanisms of fatigue’). Accordingly, without some evidence of exercise-induced respiratory muscle fatigue (RMF), the argument in favour of training these muscles is flimsy at best.

Respiratory muscles are separated functionally according to whether they have inspiratory or expiratory actions. Since breathing demands equal movement of inspiratory and expiratory air, one might predict that fatigue would be present in both groups of muscles under the same conditions. This is not the case. One reason for this is the fact that inspiratory muscle work is always greater than expiratory work (recall the party balloon analogy from Ch. 1 – the stretching of tissues on inhalation assists exhalation); a second reason is the differing training state of the muscles themselves (expiratory muscles are engaged in many postural activities that improve their training status); a third reason is that different exercise conditions overload the inspiratory and expiratory muscles to differing extents.

The earliest reports of inspiratory muscle fatigue (IMF) following competitive sports events appeared in the early 1980s. In this context fatigue was defined as a loss of voluntary force generating capacity post-exercise, and a significant decrease in inspiratory muscle strength (MIP) was measured following marathon running (Loke et al, 1982). Subsequent studies have confirmed this finding (Chevrolet et al, 1993; Ross et al, 2008), as well as showing IMF after ultra-marathon (Ker & Schultz, 1996) and triathlon competitions (Hill et al, 1991).

Under laboratory and field-based research conditions, IMF has been demonstrated following rowing (Volianitis et al, 2001; Griffiths & McConnell, 2007), cycling (Romer et al, 2002b) and swimming (Lomax & McConnell, 2003), as well as a sprint triathlon (Sharpe et al, 1996) and treadmill marathon running (Ross et al, 2008). All of the studies cited above have evaluated IMF using maximal inspiratory pressure (MIP) measured at the mouth, which is a holistic, voluntary surrogate of inspiratory muscle force production (see Ch. 6 for a description of MIP assessment). Although MIP has its merits (being non-invasive, portable, quick and easy to administer, reliable and holistic), it can also be criticized for being susceptible to the influence of changes in effort. In other words, immediately after exercise a lower MIP might be the result of reduced effort, and not due to physiological factors. However, contractile fatigue of the diaphragm has also been confirmed in the laboratory following heavy exercise using electrical and magnetic stimulation of the phrenic nerves (Johnson et al, 1993; Mador et al, 1993; Babcock et al, 1997; Babcock et al, 1998). Thus, not only is there evidence of IMF following real world sports participation and laboratory simulations of competition, but rigorous laboratory trials also demonstrate specific contractile fatigue of the diaphragm after heavy exercise. The observation that the diaphragm was susceptible to exercise-induced fatigue initiated a process that has led to a complete rethink about the role of respiratory muscles in exercise limitation (Romer & Polkey, 2008).

But what of the expiratory muscles? The effect of real world sports activities upon expiratory muscle function has been studied much less extensively, and existing data are currently contradictory. Following marathon running that induced a fall in MIP, no change in maximal expiratory pressure (MEP) was observed post-exercise (Chevrolet et al, 1993; Ross et al, 2008). Similarly, following a triathlon that elicited a significant fall in MIP, there was no change in MEP (Hill et al, 1991). In contrast, following a rowing time trial that simulated a 2000-metre rowing race in the laboratory, a significant decline in MEP was observed (Griffiths & McConnell, 2007). Similarly, under laboratory conditions where cycling exercise was performed to the limit of tolerance (T_lim), MEP was shown to decline (Cordain et al, 1994). In contrast, some authors observed no change in MEP following maximal cycle ergometer exercise, but did observe a fall in MIP (Coast et al, 1999). Non-volitional assessment of expiratory muscle fatigue (EMF) using magnetic stimulation of abdominal muscles has recently demonstrated EMF occurring after high-intensity cycle ergometer exercise to T_lim (Taylor et al, 2006; Verges et al, 2006). Thus, it appears that EMF may be specific to certain exercise modalities and / or intensities of exercise. These conditions appear to be characterized by exercise at maximal intensity, and / or situations in which the expiratory muscles have a key role in propulsive force transmission, such as rowing.

Collectively, the literature points to IMF occurring in response to a wider range of activities than EMF, and possibly also at lower intensities and / or following shorter durations of activity.

The next question to consider is whether there are any functional repercussions of RMF. This has been studied using a variety of experimental designs, but principally by using two basic approaches: first by inducing RMF and studying its influence upon subsequent exercise, and second by manipulating the work of breathing during exercise to accelerate RMF (by adding a resistance to breathing) or to delay the time to RMF (by using a ventilator to undertake the work of breathing). The effects of prior IMF and EMF are to increase the intensity of breathing effort during subsequent whole-body exercise, and to lead to a shorter time to T_lim during constant power output exercise. For example, one of the first studies to examine the effect of prior IMF on exercise tolerance observed a 23% reduction in the ability to sustain cycling at 90% of maximal oxygen uptake (Mador & Acevedo, 1991). There was an increase in the sensation of effort during exercise, i.e., exercise after IMF felt harder. Using a slightly different experimental design, the effects of prior IMF on isolated plantar flexor exercise have been studied (McConnell & Lomax, 2006). In this case, a more rapid fatigue of the plantar flexor muscles was observed after IMF (the reasons for this are explained later).

More recently, the effects of prior EMF on cycling performance were assessed (Taylor & Romer, 2008). A decrease in T_lim (33%) was observed when exercise followed EMF, as well as an increase in the perceptions of both breathing and leg effort. Leg fatigue was also more severe after EMF. However, a note of caution is required in the interpretation of studies that have pre-fatigued the expiratory muscles. The same authors have also shown that expiratory loading induces simultaneous IMF and EMF (Taylor & Romer, 2009). In other words, the effect of EMF on subsequent exercise performance is ‘contaminated’ by accompanying IMF. This is because the inspiratory muscles are involved in the transmission of expiratory pressure. Thus, any effects of EMF on performance cannot be ascribed solely to the expiratory muscles.

On the face of it the observations that IMF, and possibly also EMF, exacerbates limb muscle fatigue defy logical explanation; after all, why should fatiguing the respiratory muscles exacerbate fatigue in the limb muscles? The answer lies in the findings of a series of studies that have examined the influence of manipulating the work of breathing during exercise. In theory, if respiratory muscle work limits exercise performance, then reducing the amount of work they undertake during exercise should improve performance. Similarly, increasing the work of breathing during exercise should impair performance. In a series of very elegant studies undertaken during the mid-1990s, a proportional assist ventilator was utilized to ‘unload’ the inspiratory muscles during exercise, whilst a flow resistor was used to increase inspiratory muscle work.

In the first study to explore the impact of the work of breathing on exercise tolerance, the influence of changes in the work of breathing upon leg blood flow during maximal cycle ergometer exercise was examined (Harms et al, 1997). A reciprocal relationship between leg blood flow and the work of breathing was observed, such that when the inspiratory work was undertaken by a ventilator there was a 4.3% increase in leg blood flow. In contrast, when inspiratory work was increased by a flow resistor the leg blood flow decreased by 7%. The changes in leg blood flow were mediated by changes in the neural input to the blood vessels in the limbs, resulting in vasoconstriction when inspiratory work was increased and dilatation when it was reduced. In a series of subsequent studies, it was shown that the stimulus for limb vasoconstriction was a cardiovascular reflex originating within the inspiratory muscles, which became known as the ‘inspiratory muscle metaboreflex’ (St Croix, 2000; Sheel et al, 2001; Sheel et al, 2002). The findings of these studies have been replicated and extended to provide compelling evidence that functional overload of the inspiratory muscles induces reflex cardiovascular adjustments that reduce exercising limb blood flow (McConnell & Lomax, 2006; Katayama et al, 2012). The exercise models employed by early studies suggested that only very-high-intensity exercise was associated with inspiratory muscle metaboreflex activation (Wetter et al, 1999). However, more recent studies have shown that moderate-intensity exercise combined with inspiratory muscle loading also leads to inspiratory metaboreflex activation (Katayama et al, 2012), suggesting that the critical factor is functional overload of the inspiratory muscles, not the whole body muscle intensity.

The ‘inspiratory muscle metaboreflex’ is activated when metabolite accumulation within the inspiratory muscles stimulates afferent nerve fibres (type III and IV) to increase their firing frequency. Stimulation of these fibres precipitates an increase in the strength of sympathetic efferent outflow, which induces a generalized vasoconstriction. Limiting blood flow restricts the supply of oxygen and impairs the removal of exercise metabolites from exercising muscles, with the result that muscles fatigue more quickly and exercise performance is impaired (McConnell & Lomax, 2006). Indeed, this is precisely what has been found; changes in leg blood flow elicited by increasing or reducing the work of inhalation are correlated with changes in the magnitude of exercise-induced leg fatigue (Romer et al, 2006). In other words, increasing the work of inspiration reduces leg blood flow, exacerbates leg fatigue and impairs exercise tolerance, whereas reducing the work of inhalation does the opposite. However, it is important to appreciate that contractile fatigue of the inspiratory muscles is not an essential prerequisite to metaboreflex activation; the prerequisite is metabolite accumulation, which may not necessarily induce contractile fatigue. Indeed, it has been argued that muscle feedback may provide an important protective mechanism that guards against fatigue (Gandevia, 2001). The findings summarized above complete the circle that links RMF with leg fatigue, i.e., metaboreflex activation precipitates limb vasoconstriction, reducing limb blood flow and accelerating limb fatigue. The evidence for an effect of IMT upon metaboreflex activation will be reviewed in Chapter 4.

Earlier, we touched briefly upon the effect of IMF and EMF on breathing and limb effort, i.e., RMF intensifies sense of effort during exercise (Mador & Acevedo, 1991; Taylor & Romer, 2008). The influence upon limb effort should now be clear: IMF reduces limb blood flow, thereby reducing oxygen delivery and accelerating limb fatigue. Although it might seem self-evident that weak or fatigued muscles generate greater perception of effort than fresh or stronger muscles, the neurophysiological mechanism underpinning this reality merits a few words. The human brain is able to judge the size of the outgoing neural drive (McCloskey et al, 1983), and as muscles contract they return information to the brain about the amount of force that is being generated, as well as the speed and range of motion of the movement (Cafarelli, 1982). Heavy objects require high forces, they can be moved only slowly and may impose a limited range of motion; the opposite is true for light objects. The sensory area of the brain compares the size of the drive sent to the muscles with the sensory information coming from the muscles. In doing so, it formulates a perception of effort. The size of the neural drive required to generate a given external force is influenced by a number of factors, but principally by the strength of the muscle. A strong muscle requires a lower neural drive to generate a given force, which is why weights feel lighter after strength training. Similarly, a fatigued muscle requires a higher neural drive to generate a given force, which is why weights feel heavier when muscles are fatigued (Gandevia & McCloskey, 1978).

As was described in Chapter 1, the neurophysiological principles described above apply equally to the respiratory muscles (Campbell, 1966) as they do to other skeletal muscles. Thus, weakness, fatigue, or indeed strengthening, of the respiratory muscles modulates the perception of breathing effort and dyspnoea. Similarly, abnormalities of respiratory mechanics exacerbate perception of breathing effort (Scano et al, 2010). Recently, the term ‘neuromechanical uncoupling’ has been used to describe the imbalance between neural drive and the mechanical events that it produces (see Ch. 1).

Finally, it is worth mentioning some emerging evidence about the influence of group III and IV afferent feedback upon the central perception of effort and central fatigue. Group III and IV fibres project to a number of sites within the central nervous system. Most recently, Amann and colleagues employed a selective μ-opioid receptor agonist to demonstrate, for the first time, that afferent feedback from locomotor group III and IV fibres makes an ‘essential contribution’ to both cardiorespiratory control and perceptual responses in the exercising human being (Amann et al, 2010a). The latter finding is consistent with the observation that strengthening inspiratory muscles attenuates both respiratory and peripheral effort perception (Romer et al, 2002a), which may arise because of reduced feedback from group III and IV afferents in both respiratory and locomotor muscles.

Furthermore, feedback from group III and IV afferents is also implicated in central fatigue mechanisms, via inhibition of central motor output (Gandevia, 2001). It has been suggested that afferent feedback from exercising muscles protects locomotor and respiratory muscles from catastrophic fatigue (Gandevia, 2001). Indeed, Gandevia suggested, ‘An extreme example [of central fatigue] occurs with exercise of the inspiratory muscles in which task failure can occur with minimal peripheral fatigue’ (Gandevia, 2001). The importance of group III and IV afferent feedback in regulating integrated exercise responses was illustrated recently by a study in which a cycle time trial was undertaken with and without the selective μ-opioid receptor agonist fentanyl (Amann et al, 2009). During a self-paced 5 km time trial, intrathecal fentanyl was associated with greater quadriceps fatigue, a higher central motor output and greater perceived exertion compared with placebo. A higher power output in the first half of the fentanyl time trial was offset by a lower power output in the second, resulting in no change in performance time. However, compared with placebo, the decline in quadriceps twitch force was greater with fentanyl (45.6% vs 33.1%) and was associated with ambulatory problems post-exercise. The authors suggest their data ‘emphasize the critical role of locomotor muscle afferents in determining the subject's choice of the “optimal” exercise intensity that will allow for maximal performance while preserving a certain level of locomotor muscle “functional reserve” at end-exercise’ (Amann et al, 2009). The specific contribution of respiratory muscle group III and IV afferents to central fatigue during whole-body exercise awaits investigation. Given the importance of protecting diaphragm function, it is reasonable to speculate that the inhibitory feedback from diaphragm afferents during exercise influences both respiratory and locomotor central motor output.

Thus, the past decade has seen the emergence of evidence that respiratory muscle work has influences far beyond anything that was thought possible. The respiratory muscles can contribute to exercise limitation through their influence on cardiovascular reflex control, i.e., metaboreflex reduction of limb blood flow. In addition, the respiratory muscles make a potent contribution to the perception of effort during exercise, and may also play a role in central fatigue. The evidence that strengthening the respiratory muscles reduces effort perception and improves exercise tolerance is reviewed in Chapter 4.

In this section we have considered the limitation to exercise tolerance imposed by the respiratory muscles in healthy people. The following section will describe how disease-specific factors limit exercise by exacerbating the breathing-related limitations to exercise tolerance that exist in healthy people. In Chapter 4 we will consider the evidence that rebalancing the relationship between demand and capacity of the respiratory pump muscles using RMT induces beneficial adaptations to respiratory muscle structure and function, as well as clinical benefits.

Respiratory disease

Chronic heart failure and pulmonary hypertension

Dyspnoea and exercise intolerance are hallmarks of chronic heart failure (CHF), with patients experiencing high levels of dyspnoea and limb discomfort at relatively low intensities of exercise (Wilson & Mancini, 1993). The complexity of the syndrome of CHF is such that the contribution of individual abnormalities to exercise intolerance is impossible to isolate. However, since dyspnoea is such a potent contributor to exercise intolerance in CHF, it is clear that the pulmonary contribution is extremely important. More specifically, evidence has emerged over the past decade implicating inspiratory muscle function and the demand / capacity relationship of the inspiratory muscles as important contributors to exercise intolerance in CHF (Ribeiro et al, 2012).

The causes of exertional dyspnoea in CHF and COPD have at least one common denominator: a high demand for inspiratory muscle work. As was described in the earlier section ‘Changes in breathing mechanics and respiratory muscle function’, this increased demand is multifactorial in CHF, being due to an exaggerated ventilatory response, tachypnoeic breathing pattern, increased lung compliance and expiratory flow limitation. Coupled to this increased demand is a reduced capacity for inspiratory muscle work, due to inspiratory muscle dysfunction (Ribeiro et al, 2012). In addition, patients with CHF also have to contend with a severely compromised cardiac output (Pina et al, 2003). The influence of CHF per se upon cardiac output and blood flow is not limited to the pulmonary circulation. During exercise, muscle blood flow is impaired leading to a reduction in oxygen delivery and metabolite removal, with the result that there is a greater reliance upon anaerobic metabolism. This has implications for the inspiratory muscles, as the resulting metabolic acidosis stimulates an increase in _E (Franco, 2011). Patients with CHF also have greater chemoreflex sensitivity, causing an increase in the ventilatory response to chemoreflex activation as well as in muscle sympathetic nerve activity (Ribeiro et al, 2012). Furthermore, there is also evidence that competition for a share of the limited cardiac output results in underperfusion and deoxygenation within the inspiratory muscles during exercise (Mancini et al, 1991; Terakado et al, 1999).

In patients with CHF, the exercise hyperpnoea is associated with a high demand for inspiratory pressure relative to the capacity to generate pressure (MIP), as well as a high level of inspiratory neural drive (Vibarel et al, 1998). Given these conditions, and the evidence that accessory muscle perfusion is compromised (Mancini et al, 1991), one would predict a propensity for inspiratory muscle fatigue in patients with CHF. As is the case in COPD, exercise-related alterations in inspiratory muscle function have been studied relatively little in patients with CHF, and almost exclusively in terms of diaphragm contractile function. One study found no change in twitch diaphragm pressure (TwP_di) after a symptom-limited cycle ergometer test in patients with CHF (Kufel et al, 2002). In this study, four patients reported terminating exercise due to dyspnoea, whilst six stopped because of leg fatigue. The absence of post-exercise diaphragm fatigue was confirmed in a later study employing an incremental cycle test to the limit of tolerance (Dayer et al, 2006). However, these data need to be interpreted carefully as there is evidence that the work of breathing most likely contributes to leg fatigue (Dempsey, 2010). Furthermore, the absence of diaphragm fatigue may also be explained by the support provided by inspiratory accessory muscles in delivering the required exercise hyperpnoea, thereby protecting the diaphragm from fatigue (see above section on COPD). As has been shown for patients with COPD, there is evidence to support the existence of accessory muscle fatigue following exercise in patients with CHF; furthermore, this fatigue appears to be related to their dyspnoea (Hughes et al, 2001). In a study of CHF patients who walked to the point of intolerable dyspnoea, inspiratory muscle relaxation rate was slowed, providing evidence for global inspiratory muscle fatigue (Hughes et al, 2001). These authors concluded that their observations were consistent with an imbalance between the demands placed on the inspiratory muscles and their capacity to meet this demand.

The limiting role of inspiratory muscles in patients with CHF is also supported by evidence that reducing the work of breathing during exercise improves exercise tolerance. When patients with CHF breathed heliox during an incremental exercise test, there was an increase in the time to the limit of tolerance (Mancini et al, 1997). Furthermore, when patients with CHF receive inspiratory assistance during exercise (partial inspiratory muscle unloading with pressure support), the time to the limit of tolerance during a constant load cycle test is increased (O'Donnell et al, 1999). The latter was also accompanied by a reduction in leg discomfort.

These data are similar to those in healthy athletes during assisted breathing, in whom improvements in exercise tolerance are ascribed to the absence of inspiratory muscle metaboreflex activation (Harms et al, 1997). Accordingly, a reduction in perception of leg effort during exercise with assisted breathing is due to improved leg blood flow. Indirect support for this comes from a study that confirmed the finding that inspiratory muscle unloading improves exercise tolerance and reduces leg effort in patients with CHF, but also found that these changes were associated with improved leg oxygenation (Borghi-Silva et al, 2008a). The same group has made identical observations in patients with COPD (Borghi-Silva et al, 2008b). Direct evidence comes from the improvement in limb blood flow observed when patients with CHF cycle (60% peak power) with inspiratory muscle unloading (Olson et al, 2010); however, unlike healthy people, when the inspiratory muscles of people with CHF were loaded, there was no reduction in limb blood flow above that observed during normal breathing. Thus, patients with CHF were unable to intensify the sympathetic output to limb vasculature when the work of breathing was increased, suggesting that this output is already maximal during normal breathing. These data provide support for the role of the inspiratory muscle metaboreflex in exercise limitation in patients with CHF. It is reasonable to suggest that, in patients with a compromised cardiac output, this reflex may play a particularly potent role in exercise limitation.

Resting indices of cardiac function have been shown to be poor predictors of exercise tolerance in patients with CHF; this is in contrast to the excellent predictive power of indices of respiratory function (Faggiano et al, 2001). The primary importance of inspiratory muscle function as a contributor to exercise intolerance in patients with CHF is supported by the observation that peak oxygen uptake is correlated with MIP (but not MEP) (Nishimura et al, 1994; Chua et al, 1995), as well as with inspiratory capacity (Nanas et al, 2003). Inspiratory capacity was also an independent predictor of exercise tolerance, and was correlated with pulmonary capillary wedge pressure (a determinant of lung compliance). The former study (Chua et al, 1995) illustrates the important role of inspiratory muscle capacity, and the latter (Nanas et al, 2003) of the demand for inspiratory muscle work in determining exercise tolerance in patients with CHF.

In Chapter 4, the evidence that inspiratory muscle training improves exercise tolerance in patients with CHF is reviewed.

Neurological and neuromuscular disease

Obesity

Exertional dyspnoea is a common symptom in obese patients (Babb et al, 2008a), but it has been studied comparatively little from a mechanistic perspective. Extreme dyspnoea is not a limiting symptom in all obese patients, but a key underlying factor in determining the severity of dyspnoea appears to be the oxygen cost of breathing (Babb et al, 2008a). When the relationship between the oxygen cost of breathing and exertional dyspnoea was examined directly in obese women, the oxygen cost of breathing was found to be considerably and significantly higher (38–70%) in those who were breathless upon exertion (Babb et al, 2008a). Furthermore, around 65% of the variation in dyspnoea was explained by the variation in the oxygen cost of breathing. These findings are consistent with the notion that dyspnoea is directly related to the work of the respiratory muscles. Since work is elevated in the face of relatively normal inspiratory muscle strength, dyspnoea reflects an imbalance between the demand for inspiratory muscle work and the ability of the inspiratory muscles to meet that demand (Campbell, 1966).

An important factor that appears to influence the total oxygen cost of exercise in obese individuals is fat distribution. For example, obese women (mean BMI 40 kg·m^− 2) in whom fat was deposited in the upper body (UBD) had a greater oxygen cost of cycling, a higher _E, a more rapid and shallow breathing pattern and a lower anaerobic threshold than women whose fat was distributed in the lower body (Li et al, 2001). This suggests an underlying mechanism related to the higher work of breathing when fat is deposited in and around the trunk. Although dyspnoea was not assessed during this study (Li et al, 2001), it is reasonable to presume that it would have been higher in the UBD group.

The question then arises as to the extent of limitation imposed by dyspnoea and the relationship of this to the performance of the inspiratory muscles. In a study of obese men (mean BMI 42 kg·m^− 2), an index of the relative work of breathing has been created by referencing the work of breathing to the capacity of the inspiratory muscles to sustain work (Chlif et al, 2007). In addition, an index of the neural drive to the inspiratory muscles was assessed. The obese men had higher levels of inspiratory neural drive and dyspnoea at the same relative intensity of exercise compared with non-obese men. As is typical, the obese men also adopted a rapid shallow breathing pattern as part of their strategy to minimize respiratory discomfort. However, the strategy did not appear to normalize their dyspnoea, because the relative work of breathing remained too high for the inspiratory muscles, as evidenced by the inspiratory muscle fatigue that was present post-exercise. These data once again reinforce the fact that obese individuals have an imbalance between demand and capacity for inspiratory muscle work.

The inspiratory muscle fatigue observed in the study of Chlif et al (2007) and the high levels of inspiratory muscle work mean that the risk of inspiratory muscle metaboreflex activation is likely to be very high in obese individuals. The repercussions of this were described in the section ‘Healthy people’, and include a reduction in limb blood flow, leading to increased rate of development and magnitude of both limb discomfort and limb muscle fatigue.

To date, the interrelationships of dyspnoea, inspiratory muscle work and exercise tolerance in obesity have been studied only using cycle ergometer exercise. This modality is used because it minimizes the influence of the obese participants’ body mass. However, in the real world, obese patients are required to walk, which not only requires them to cope with the increased metabolic and ventilatory demands imposed by their increased mass, but also increases the requirement to engage the postural role of the respiratory muscles. These factors are inescapable, exacerbating the demands placed upon these muscles, resulting in dyspnoea, inspiratory muscle overload and, perhaps, accelerated limb fatigue due to inspiratory muscle metaboreflex activation.

In Chapter 4, the evidence that respiratory muscle training improves exercise tolerance in patients with obesity is reviewed.

Ageing

The senescent changes to the pulmonary system have been dubbed ‘senile emphysema’ (Janssens et al, 1999). Accordingly, it is no surprise that exertional dyspnoea is a common complaint amongst the elderly, even in the absence of cardiopulmonary disease (Landahl et al, 1980). Furthermore, the intensity of dyspnoea is higher by 1 to 2 Borg units at a standardized submaximal oxygen uptake during incremental treadmill exercise in healthy elderly (60–80 years) adults compared with younger (40–59 years) adults (Ofir et al, 2008).

However, dyspnoea perception in healthy, active older people does not appear to be correlated with expiratory flow limitation or _E; instead it appears to be related to the relative load upon the inspiratory muscles, i.e., the inspiratory pressure requirement as a percentage of inspiratory pressure-generating capacity – in other words, the state of the demand / capacity relationship (Johnson et al, 1991). The requirement for inspiratory pressure generation during exercise is increased in healthy ageing by a number of factors, including a higher requirement for _E, dynamic lung hyperinflation and mechanical constraints on V_T expansion (Jensen et al, 2009a). Furthermore, inspiratory muscle strength declines with advancing age (McConnell & Copestake, 1999).

As was described in the earlier section ‘Healthy people’, inspiratory muscle overload can contribute to both respiratory and locomotor muscle fatigue. In healthy people, the symptoms leading to the cessation of exercise fall into two main categories: ‘local’ locomotor muscle fatigue and ‘central’ dyspnoea (Ekblom & Goldbarg, 1971). When the contributions of leg effort and dyspnoea to exercise limitation are assessed, over 60% of healthy people cease exercise because of the combined contribution of the two symptoms (Hamilton et al, 1996a). Interestingly, the Borg CR-10 rating of dyspnoea at exercise cessation in this healthy group was higher (6 units) than the rating in a similar group of patients with respiratory disease (5 units) (Hamilton et al, 1996a). These data indicate that, even in healthy people, dyspnoea is a troubling symptom that makes an important contribution to the decision to stop exercising.

In Chapter 4, the evidence that inspiratory muscle training improves exercise tolerance in healthy older people is reviewed.

Miscellaneous conditions

In the section ‘Changes in breathing mechanics and respiratory muscle function’ a wide range of disease conditions were considered, including some where respiratory limitation of exercise tolerance is irrelevant, e.g., mechanical ventilation. The following section is therefore limited to those conditions in which the demand / capacity relationship of the respiratory pump may limit exercise tolerance.

• Core stability: actions that maintain stability of the trunk and lumbopelvic region, protecting the spine from damage and creating a stable platform from which to generate limb movements.

• Postural control: actions that maintain balance in response to destabilizing forces acting upon the body.

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