Control of the depth and rate of breathing: metabolic vs. non‐metabolic inputs

We read with great interest the review paper by Tipton et al. (2017). The authors examined the ventilatory response to a wide range of stressors, with a special interest in the differential regulation of respiratory frequency (f _R) and tidal volume (V _T). Despite a clear differential control of f _R and V _T emerging from the reviewed studies, the authors highlight how their regulation was typically neglected. An exception to this is our recent work on the differential control of f _R and V _T during high‐intensity exercise (Nicolò et al. 2017), which was inspired by previous observations (Nicolò et al. 2015, 2016). Our findings fit nicely with some of the evidence reviewed by Tipton et al. (2017) despite the very different conditions explored. Therefore, the integration of information from both contributions has allowed us to expand on the breathing control perspective proposed by Tipton et al. (2017). We present here a deliberately simple viewpoint on the differential control of f _R and V _T which, despite the complexity underlying breathing control, applies in a wide range of conditions.

By manipulating recovery intensity and exercise duration during high‐intensity interval training, we found that f _R, unlike V _T, responded rapidly and in proportion to variations in workload, and was dissociated from some markers of metabolic stimuli in response to both experimental manipulations (Nicolò et al. 2017). We concluded that fast inputs (including central command) appear to contribute more than metabolic stimuli to f _R regulation. We also supported our conclusions by presenting evidence that V _T, unlike f _R, is regulated by metabolic stimuli in various non‐exercise conditions. This notion is even more convincing in the light of a number of findings reviewed by Tipton et al. (2017).

The authors report that the prototypic human response to stress (fight or flight) includes a fast increase in ventilation, mediated preferentially by f _R. This response is common to various stressors including cold, panic and pain. For instance, immersion in cold water produces the ‘cold shock response’, which includes a fast increase in minute ventilation (${\dot{V}}_{\mathrm{E}}$) primarily determined by an increase in f _R, with V _T not increasing until f _R begins to fall back towards pre‐immersion levels (Tipton et al. 1991). This f _R response is possibly driven by the dynamic response of the peripheral cold thermoreceptors determining the ‘cold shock response’, which attenuates within the first 2 min of immersion. Thereafter, the respiratory response to cold water immersion is mainly driven by the metabolic demands of shivering, which is an involuntary form of skeletal muscle contraction (Tipton et al. 2017). This alteration in the inputs driving ventilation determines a diminution of the contribution of f _R to ${\dot{V}}_{\mathrm{E}}$ and an increasing contribution of V _T, which becomes the predominant component of ${\dot{V}}_{\mathrm{E}}$ with shivering (Tipton et al. 2017).

Panic is a sudden sensation of fear or anxiety which affects ventilation through central mechanisms rather than metabolic stimuli. The evidence collected by Tipton et al. (2017) suggests that panic increases f _R, but not V _T, when it is evoked by non‐metabolic interventions. Conversely, panic increases V _T more than it does f _R when it is induced by hypercapnia, which is also a potent metabolic stimulus (Tipton et al. 2017).

Pain is an unpleasant sensory experience which affects ventilation through a mixture of behavioural response and a direct effect on medullary respiratory centres (Tipton et al. 2017). When a behavioural ${\dot{V}}_{\mathrm{E}}$ response is induced by warning the subjects of an incoming painful stimulus, anticipation of pain causes an increase in f _R (Willer, 1975). On the other hand, when the hormonal stress response induced by pain is reproduced by intravenous infusion of cortisol, adrenaline and glucagon, an increase in ${\dot{V}}_{\mathrm{E}}$ mediated by V _T – but not f _R – is observed (Weissman et al. 1986).

Collectively, the reported findings point to a non‐metabolic regulation of f _R, while V _T appears to be strongly regulated by metabolic stimuli. This is further supported by remarkable findings on animals (Borison et al. 1977) and humans (Guz et al. 1966) showing that some metabolic stimuli, including hypercapnia, have no direct effect on f _R. Instead, the increase in f _R observed with severe levels of hypercapnia may be evoked by volume feedback, panic and other behavioural responses induced by hypercapnia (Tipton et al. 2017). Therefore, for those conditions where f _R seems to partly respond to metabolic stimuli, potential alternative explanations should be considered. On the other hand, f _R seems to be primarily regulated by fast inputs, some of which may not contribute substantially to regulating V _T. In this context, fast inputs are central command and other brain inputs (e.g. from brain areas involved in emotional processing), muscle and other non‐chemical afferent inputs driving ventilation. Temperature is another non‐metabolic stimulus which has a strong effect on f _R, but the underlying mechanisms need further clarification (Tipton et al. 2017). For a series of additional aspects that can affect the ventilatory pattern (e.g. mechanical aspects), the reader is referred to Tipton et al. (2017).

The fact that f _R and V _T are regulated by different inputs may also help explain why they differ in the timing of their responses. With the onset of a variety of stressors (Tipton et al. 2017) including exercise (Nicolò et al. 2017), a fast increase in f _R and a delayed response of V _T is often observed. Among respiratory physiologists, it is commonly proposed that fast inputs drive the rapid increase in ventilation in such conditions, while metabolic stimuli fine‐tune the control of ventilation in order to meet the metabolic requirements. We propose that the fast increase in ${\dot{V}}_{\mathrm{E}}$ is guaranteed by a preferential regulation of f _R, while the fine‐tuning role is played by V _T. Therefore, f _R and V _T can be respectively regarded as the behavioural and metabolic components of ${\dot{V}}_{\mathrm{E}}$. This differential control of f _R and V _T is particularly favourable if we consider how they affect alveolar ventilation (Tipton et al. 2017).

While we acknowledge that our interpretation of the control of f _R and V _T is a simplification of the complex regulation of breathing, it has important implications for teaching and future research in different disciplines.

Additional information

Competing interests

None declared.

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