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Symposium Reports |
1 Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, UK
Abstract
Below the lactate threshold (
L), ventilation 
responds in close proportion to CO2 output 
to regulate arterial partial pressure of CO2
. While ventilatory control models have traditionally included proportional feedback (central and carotid chemosensory) and feedforward (central and peripheral neurogenic) elements, the mechanisms involved remain unclear. Regardless, putative control schemes have to accommodate the close dynamic ‘coupling’ between 
and 
. Above L, 
is driven down to constrain the fall of arterial pH by a compensatory hyperventilation, probably of carotid body origin. When 
requirements are high (as in highly fit endurance athletes), 
can attain limiting proportions. Not only does this impair gas exchange at these work rates, but there may be an associated high metabolic cost for generation of respiratory muscle power, which may be sufficient to divert a fraction of the cardiac output away from the muscles of locomotion to the respiratory muscles, further compromising exercise tolerance.
(Received 18 December 2006;
accepted after revision 15 January 2007; first published online 18 January 2007)
Corresponding author S. A. Ward: Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, UK. Email: s.a.ward{at}leeds.ac.uk
In humans, ventilation 
during moderate exercise (below the lactate threshold, L) regulates the arterial partial pressure of CO2
at, or close to, resting levels through a close proportional matching to pulmonary CO2 output (
; reviewed by Whipp & Ward, 1991). Above L, there is the additional challenge of effecting respiratory compensation to constrain the fall of arterial pH (pHa) that results from the metabolic (largely lactic) acidosis (Wasserman & Casaburi, 1991) and, in some highly fit endurance athletes, also constraining the degree of exercise-induced arterial hypoxaemia (EIAH) that can emerge at higher work rates (WRs; reviewed by Dempsey & Wagner, 1999; Dempsey, 2006; Stickland & Lovering, 2006).
Ventilatory requirements
Recognizing that 
responds more closely to the demands for CO2 clearance than O2 uptake, the associated ventilatory requirements at any particular work rate (WR) are dictated via the Fick principle; i.e.
|
| (1) |
is alveolar ventilation, 
is pulmonary CO2 output and 863 is the constant which corrects for the transformation of fractional concentration to partial pressure and the convention of ventilatory volumes being defined at BTPS (body temperature and pressure, saturated with water vapour) while volumes of metabolically exchanged CO2 (and O2) are defined at STPD (standard temperature, 0°C, and pressure, 760 mmHg, dry). Regulation of 
requires 
to increase in a fixed proportion with 
, i.e. yielding a linear 
relationship. Above L, 
is augmented by bicarbonate (HCO3–)-mediated buffering in response to the metabolic acidosis and by compensatory hyperventilation that lowers 
as a result of CO2 being washed out of the rapidly exchanging body stores. This lowering of the 
‘set-point’ results in a steepening of the 
relationship. Note that a given increment of 
becomes less effective at: (i) reducing 
from a fixed set-point (e.g. 40 mmHg) as 
increases (Fig. 1, c 
a b); and (ii) reducing 
from a lower initial set-point (e.g. 30 versus 40 mmHg) at a fixed level of 
, as might occur with ascent of a lowland native to high altitude (Fig. 1, b e; Whipp & Pardy, 1986).
|
|
| (2) |
The value of VD/VT normally decreases with increasing WR, reflecting the proportionally smaller end-inspiratory expansion of the conducting airways relative to the total lung volume increase (e.g. Jones et al. 1966; Wasserman et al. 1967). It follows from eqn (2) that the 
requirement also increases as a linear function of 
at any CO2 set-point, as long as VD/VT adopts a hyperbolic response characteristic (Whipp & Ward, 1982; Fig. 2):
|
| (3) |
-intercept, respectively, of the 
relationship.
|
requirement for any particular WR therefore reflects the combined influence of three defining variables: pulmonary CO2 clearance 
; the set-point for 
regulation; and the efficiency of pulmonary gas exchange (1 –
VD/VT). This is illustrated in Table 1 by some reasonable scenarios. For example, Row 1 represents a young, highly fit endurance athlete with a maximum 
of 6 l min–1 who is exercising at a sub-L WR 
with a normal 
of 40 mmHg and a modest reduction in VD/VT (from a resting value of 
0.3; Jones et al. 1966; Wasserman et al. 1967). This subject will therefore have a 
requirement approximately half that of an elderly ‘Masters’ endurance athlete exercising at the same absolute 
, but where this 3 l min–1 value is the athlete's 
(row 2). The elderly subject will therefore manifest an additional 
requirement consequent to the compensatory hyperventilation for the metabolic acidosis, causing the 
set-point to be lowered to 30 mmHg. The slight increase in VD/VT in this subject reflects the influence of the age-related loss of lung recoil on pulmonary gas exchange (reviewed by Johnson & Dempsey, 1991; Dempsey et al. 1996). In contrast, when the young athlete is exercising at 
(row 3), with a similar degree of compensatory hyperventilation and, of course, a lower VD/VT (e.g. 0.1; see Jones et al. 1966; Wasserman et al. 1967), the 
requirement is now over 50% greater than that of the elderly athlete. Were the young athlete to be exercising at high altitude (row 4) and therefore with an additional ventilatory drive from arterial hypoxaemia (imposing a further reduction in CO2 set-point), the 
requirement would increase further despite 
probably being somewhat reduced. Thus, simultaneous changes in these three defining variables can elicit major variations in the level of exercise 
which can, if of sufficient magnitude, attain limiting proportions and compromise exercise tolerance.
|
The mechanisms subserving ventilatory control in exercise remain controversial, but traditionally are proposed to include elements of proportional feedback (central and carotid chemosensory) and feedforward (‘central command’ and muscle reflex) control in varying proportions (reviewed by Whipp & Ward, 1991; Kaufman & Forster, 1996; Dempsey, 2006; Waldrop et al. 1996, 2006). However, the dynamic behaviour of 
in response to WR forcing functions such as steps, ramps, impulses and sinusoids provides important intensity-dependent clues to the likely operation of this control (reviewed by Whipp & Ward, 1991; Ward, 2000).
The 
response to moderate-intensity step exercise has three temporal components: an initial rapid ‘phase 1’ component, which is followed by a slower exponential ‘phase 2’ component that leads to the steady state (‘phase 3’). Owing to its immediacy and speed, the phase 1 
increase at the onset of step exercise has been argued to be neurally mediated. However, an alternative scheme is that of cardiodynamic control, whereby the increased in cardiac output 
at exercise onset has been proposed to evoke a proportional (and zero-order) reflex activation of 
, with end-tidal 
and 
remaining essentially stable (Wasserman et al. 1974). Unlike classical neurogenesis, this proposal can better accommodate the conversion of the phase 1 hyperpnoea from an abrupt step-like profile to one which is smaller and more sluggish simply by imposing the same exercise challenge from prior unloaded pedalling rather than rest (reviewed by Whipp & Ward, 1991), i.e. 
demonstrating a similar change in response profile (Loeppky et al. 1981; Miyamoto, 1989). One cannot rule out, of course, that these increases in 
and 
simply develop in parallel from a common neurogenic drive (Whipp & Ward, 1982), but one whose features would necessarily be predicated to change with the initial exercise condition. More recently, however, the operational focus has shifted from the central circulation to the skeletal muscles themselves, involving alterations in intramuscular vascular tissue pressure and/or conductance (reviewed by Haouzi et al. 2004).
The fact that 
in phase 2 responds with first-order kinetics that are only slightly slower than those of 
but considerably slower than those for O2 uptake 
for a range of WR forcing functions, such as the step, impulse and sinusoid (e.g. Linnarsson, 1974; Miyamoto, 1989; Whipp & Ward, 1991; Fig. 3), has important implications for ventilatory control. The associated small transient increase in 
during on-transient phases of response, which is consistently seen when dynamic sampling resolution is high (Whipp et al. 1977; Fig. 3), clearly rules out any likelihood that the 
response is simply driving 
(i.e. hyperventilation), and instead favours some form of 
-related control. This proposition is supported by several sources of evidence (reviewed by Whipp & Ward, 1991; Ward, 2000). For example, prior volitional hyperventilation designed to acutely decrease the rapidly exchanging body CO2 stores leads to an appreciable slowing of the 
response, with the 
response also being slowed. Also, the demonstration that the linear relationship between peak-to-mean 
and 
for sinusoidal exercise of various frequencies extrapolates to the origin (Whipp et al. 1977; Fig. 3) is telling, in that the lack of a positive 
-intercept would suggest that there is no sustained 
drive that cannot be ascribed to 
(as a proxy, at least) or some function that changes with similar dynamics. In support of this is the demonstration that, during resting–recovery off-transients when the legs are no longer moving (i.e. when there is presumably no longer any central command or peripheral neurogenic drive), the dynamic 
relationship is indistinguishable from that during exercise (reviewed by Whipp & Ward, 1991). Furthermore, when a fraction of the hyperpnoea during steady-state exercise is caused to be subserved by proportional-assist positive-pressure ventilation (PAV), a compensatory reduction in 
drive ensues to restore 
back to control levels, despite central and peripheral neurogenic drives presumably being unaffected (Poon et al. 1987; Fig. 4). It is difficult to reconcile these several observations with a significant role for conventional zero-order neurogenic feedforward mechanisms in the control process.
|
|
and 
might be effected (e.g. Whipp & Ward, 1991; Dempsey, 2006). The phase 2 hyperpnoea has traditionally been ascribed to chemosensory mechanisms, argued to provide a ‘fine tuning’ for arterial blood-gas and acid–base regulation. However, the lack of sustained humoral error signals calls into question any appreciable contribution from conventional chemoreception (reviewed by Whipp & Ward, 1991; Ward, 2000), although an 20% contribution to the steady-state hyperpnoea from the carotid bodies has been demonstrated using the Dejours' O2-switching technique (Whipp & Wasserman, 1980). Interestingly, carotid chemoreceptor activation (e.g. by acute inhalational hypoxia) causes an appreciable speeding of phase 2 
kinetics, with maintained exponentiality of response despite a substantial increase in gain (Griffiths et al. 1986), i.e. first-order behaviour is retained.
An interpretational challenge arises from what appear to be elements of system redundancy in the ventilatory control process. That is, selective (or reasonably so) inactivation of any one of several putative mechanisms (e.g. via spinal cord transaction, cardiac denervation or carotid body resection) seems to have little impact on 
(reviewed by Whipp & Ward, 1991; Ward, 2000). Alternative explanations have been sought in novel control schemes involving, for example, the ‘optimization’ of humoral and respiratory-mechanical ventilatory ‘costs’ (Poon, 1983) and long-term (i.e. adaptive) modulation of the CO2 set-point (reviewed by Mitchell & Babb, 2006; although cf. Cathcart et al. 2005).
Respiratory compensation for the metabolic acidosis above L appears to be mediated largely (if not exclusively) by the carotid bodies (reviewed by Wasserman & Casaburi, 1991; Whipp & Ward, 1991; but see Dempsey, 2006 for an alternative view), although having surprisingly slow kinetics (Rausch et al. 1991; Fig. 5). To what extent this might reflect some time- or amplitude-related ‘threshold’ for chemoreceptor excitation (Whipp & Ward, 1991), possibly involving slow intracellular expression of the metabolic acidosis (Buckler et al. 1991) and/or slow signal transduction at the level of an H+-sensitive type I voltage-sensitive tandem-P-domain K+ (TASK-I) channel (Buckler et al. 2000), is presently unclear.
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Whether or not 
can satisfy its regulatory requirements may depend on the extent to which ‘constraining’ influences are operational, i.e. influences that hold 
in check while not precluding further hyperpnoea when, for example, WR increases. There is evidence, for example, that 
regulation during moderate exercise can be associated with a turbulent constraint of airflow, if 
is sufficiently high. Thus, when the inspired nitrogen is replaced by the lower-density carrier gas helium (suitably warmed in order to mask any sensation of cold in the airways), prompt hyperventilation ensues, i.e. consistent with the removal of a constraint on 
imposed by the turbulent component of airflow through the reduction in kinematic viscosity (Ward et al. 1982; Fig. 6). What is of interest from a control perspective is that, unlike inspiratory proportional-assist ventilation during moderate exercise (Poon et al. 1987; Fig. 4), there is no evidence of a compensatory reduction in 
drive during helium breathing, i.e. the hyperventilation is sustained.
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L, the compensatory hyperventilation for the lactic acidosis induces a cerebral respiratory alkalosis that might be expected to secondarily constrain 
, directly through reduced central chemoreceptor activity and possibly also indirectly via stimulation of inhibitory efferent projections to the carotid chemoreceptors (Majcherczyk & Willshaw, 1973). Ventilatory limitations
The compensatory hyperventilation above L which drives down alveolar and arterial 
and increases alveolar 
, interestingly, does not elicit a corresponding increase in arterial 
. Rather, 
typically remains unchanged, certainly in normal untrained individuals. This is a manifestation of pulmonary gas exchange becoming progressively less efficient, with the ‘ideal’ alveolar-to-arterial 
gradient (A–a
) reaching some 20–30 mmHg at high work rates (reviewed by Dempsey & Wagner, 1999). This inefficiency has been ascribed to factors such as an exacerbated regional ventilation–perfusion mismatching, diffusion limitation consequent to truncation of pulmonary capillary transit times, and increased intra- and postpulmonary shunts (reviewed by Dempsey & Wagner, 1999; Dempsey, 2006; Stickland & Lovering, 2006).
In some highly fit endurance athletes, particularly women, 
and arterial O2 saturation 
may fall (i.e. EIAH) as (A–a
) widens during progressive exercise (reviewed by Dempsey & Wagner, 1999; Dempsey, 2006; Harms, 2006; Stickland & Lovering, 2006). This can have adverse consequences for exercise tolerance; restoration of 
by means of supplemental oxygen having been shown to improve 
(Powers et al. 1989; Harms et al. 2000). In addition to gas-exchange inefficiency, an attenuated compensatory hyperventilation has been proposed to contribute to EIAH (reviewed by Dempsey & Wagner, 1999), possibly consequent to low ventilatory chemosensitivity (Harms & Stager, 1995) but more likely the result of respiratory-mechanical limitations. Indeed, the greater predisposition to EIAH in women is probably the consequence of gender-related differences in pulmonary morphology, such as a smaller thoracic and lung size, narrower airways, a smaller alveolar surface area and a smaller pulmonary capillary bed (reviewed by Harms, 2006).
While there is no evidence that 
is mechanically limited during maximal exercise in moderately fit individuals (reviewed by Beck et al. 1991; Dempsey et al. 1996; Whipp & Pardy, 1986), ventilatory control can be challenged in individuals such as elite endurance athletes who can exercise at very high WRs. That is, the ventilatory demands required to clear the associated high rates of metabolically produced CO2 and to effect respiratory compensation for the metabolic acidaemia and, in some instances, the additional drive arising from EIAH can collectively become so great that they approach, or even exceed, the mechanical limits of the lungs and chest wall (cf. Table 1). Breathing reserve, defined as the difference between the maximal voluntary ventilation (which is essentially unaffected by training status and fitness) and 
(which, while protocol specific, is increased with training), thus becomes disappearingly small or even negative. This is an expression of expiratory airflow limitation, whereby the spontaneous expiratory flow–volume (FV) curve impacts on the maximal expiratory FV (MEFV) curve (reviewed by Whipp & Pardy, 1986; Beck et al. 1991; Dempsey et al. 1996; Fig. 7). Consequently, despite further increases in ventilatory drive, 
cannot increase further, unless lung operating volumes can be increased. The ensuing CO2 retention and (further) arterial hypoxaemia predispose to compromised exercise tolerance.
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that the VT increase becomes less prominent, as the upper reaches of the pressure–volume curve are attained.
However, when expiratory flow limitation is present, EELV can actually increase (‘dynamic hyperinflation’), allowing expiration to proceed at a higher volume-specific limiting airflow (but with a less efficient inspiration consequent to the reduced resting muscle length). Dynamic hyperinflation is seen in situations where the mechanical time constant(s) for lung emptying is prolonged because of an increased respiratory-mechanical impedance, e.g. (i) in patients with chronic obstructive pulmonary disease, in whom the 
requirement at any particular (albeit low) WR is increased while 
capacity is reduced because of a disease-related loss of lung recoil (reviewed by Whipp & Pardy, 1986; Beck et al. 1991; Younes, 1991; Dempsey et al. 1996); and (ii) in highly fit elderly subjects, whose absolute 
requirement at maximum exercise is high because of their high fitness, but who also have a degree of lung recoil loss and increased small-airways resistance simply because of ageing (reviewed by Johnson & Dempsey, 1991; Dempsey et al. 1996).
What is intriguing is the presence of dynamic hyperinflation in some highly fit young individuals, in whom one might reasonably assume there to be no increase in respiratory-mechanical impedance (with the exception, perhaps, of those with a predisposition to exercise-induced reactive airways or asthma; Dempsey et al. 1996; Fig. 7). Thus, while the lung emptying profile would be expected to be normal, the point at issue is the contracted time available for expiration, consequent to a very high 
requirement and the recognition that such levels of 
are supported primarily by increases in breathing frequency (reviewed by Younes, 1991; Whipp & Pardy, 1986; Dempsey et al. 1996). It is possible that an additional component of breathing frequency increase might arise from the high levels of 
associated with such WRs. That is, the consequently increased capillary hydrostatic pressures, possibly coupled with actual ‘stress failure’ of the alveolar–capillary membrane (Hopkins et al. 1997; Ghio et al. 2006), would promote fluid exudation into the alveolar interstitial space. Expansion of the interstitial fluid volume has, in turn, been shown to be a potent stimulus to the tachypnoeic vagal J-reflex in the anaesthetized cat (e.g. Paintal, 1970). Interestingly, Kalia et al. (1973) subsequently reported that J-reflex activation in the mesencephalic cat led to an attenuation or even inhibition of walking, although this was not borne out in humans by the later study of Gandevia et al. (1998) using lobeline injection during exercise to evoke J-reflex stimulation.
There are consequences, too, of the substantial metabolic and therefore perfusion ‘costs’ associated with generating high levels of 
, consequent to factors such as turbulence, increased elastic work of breathing as end-inspiratory lung volume encroaches on the upper poorly compliant region of the compliance curve, and distortion of the chest wall (reviewed by Whipp & Pardy, 1986; Beck et al. 1991; Dempsey et al. 1996, 2006). In even moderately fit subjects, respiratory muscle blood flow at maximal exercise has been estimated to range from 4 (Whipp & Pardy, 1986) to 8 l min–1 (Bye et al. 1984), which raises the intriguing question of whether such responses can impose a perfusion-related limitation on locomotor muscle performance (which some investigators have termed ‘respiratory steal’), and vice versa. Competition between the respiratory and locomotor muscles for securing ‘adequate’ perfusion and therefore oxygenation is one of the factors proposed to contribute to diaphragmatic fatigue at sustained high WRs (reviewed by Whipp & Pardy, 1986; Dempsey et al. 1996, 2006).
Fatigue of the diaphragm at such WRs is evident from a reduction in the ratio of high-frequency to low-frequency power of the diaphragmatic electromyogram, a reduction in maximum transdiaphragmatic pressure (Pdi,max), and also a reduced Pdi,max response to supramaximal bilateral phrenic nerve stimulation relative to prior baseline values. Interestingly, this reduction in the evoked Pdi,max response was not seen in the presence of respiratory unloading by PAV (Babcock et al. 2002). Also, increasing diaphragmatic work at rest by volitionally reproducing the level and pattern of the 
response during sustained exhausting high-intensity exercise typically did not result in diaphragmatic fatigue (Babcock et al. 1995).
These observations suggest an involvement of factors in addition to the immediate respiratory-mechanical consequences of the hyperpnoea itself. A clue may reside in the demonstration that inspiratory resistive loading at near-maximal WRs reduces leg blood flow, in proportion to the increase in the work of breathing, possibly via stimulation of unmyelinated phrenic afferents by the diaphragmatic accumulation of fatigue-related metabolites that, in turn, elicits a reflex increase in sympathetic vasoconstrictor drive (Harms et al. 1997, 1998). This effect is not evident at less extreme WRs, however (Kowalchuk et al. 2002; Dempsey et al. 2006).
It should be emphasized that many of these ‘limiting’ mechanisms also contribute to excessive perceptions of shortness-of-breath or dyspnoea during exercise, whose magnitude therefore has the potential to assume limiting proportions and thus compromise exercise tolerance (Hamilton et al. 1996). Thus, high 
requirements, themselves, predispose to high levels of dyspnoea (reviewed by Killian & Jones, 1994; Dempsey et al. 1996), with the increased carotid chemoreceptor drives from metabolic acidaemia and, in some instances, arterial hypoxaemia serving to potentiate this response (Ward & Whipp, 1989). Additional influences would be expected to arise from the encroachment of tidal volume on the flat upper reaches of the compliance curve, the presence of expiratory flow limitation and fatigue of the diaphragm and possibly other muscles of respiration. Finally, interstitial oedema in the lung is a further potent dyspnoeagen, possibly involving a contribution from J-reflex activation (Paintal, 1970).
Conclusion
The challenge is therefore to discriminate between robust competing ventilatory control models that not only integrate structures within plausible physiological equivalents but also account for dynamic and steady-state system responses over a range of exercise intensities, recognizing that respiratory system limits can override the control outcomes at very high work rates.
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) as a function of CO2 output ( 
) required to effect a 10 mmHg reduction in arterial partial pressure of CO2 ( 
), from 50 to 40, 40 to 30 and 30 to 20 mmHg, to provide respiratory compensation above the lactate threshold 
), ventilatory equivalent for CO2 ( 
) and physiological dead space fraction of the breath (VD/VT) as a function of CO2 output ( 
) under isocapnic conditions 
output 
and
O2uptake 
in response to moderate-intensity sinusoidal exercise 
, 
and 
versus time for three different constant-amplitude sinusoidal work-rate frequencies (from 
versus
across all forcings (from 
, 
, 
, 
and VD/VTversus time for a single frequency (from 
and 
during moderate constant-load cycle-ergometer exercise in response to a bout of ‘assisted’ breathing (3 cmH2O l–1 s–1) 
and standard [HCO3–] to suprathreshold step exercise for three inspired oxygen fractions 
, 12% O2; •, 21% O2; 
, 80% O2). Responses expressed as changes (
) from unloaded cycling. From 
, inspiratory flow (vi), inspiratory ventilation ( 
)and tidal volume (V I) during moderate constant-load cycle-ergometer exercise in response to a bout of helium–O2 breathing 