There is growing evidence that an inadequate oxygen supply to meet demand may play a more dominant role in limiting exercise capacity in some patients with advanced COPD than impaired lung function (Aliverti et al.
2004b,
2005b; Maltais et al. 1998; Oelberg et al.
1998; Potter et al.
1971; Richardson et al.
1999; Stark-Leyva et al.
2004). In healthy subjects, limiting expiratory flow by a Starling resistor or increasing expiratory load by imposing a constant pressure at the mouth during expiration, have been shown to significantly reduce cardiac output during exercise (Aliverti et al.
2005a; Stark-Leyva et al.
2004). This results from the enforced decrease in the velocity of shortening of expiratory muscles and hypercapnia, both of which contribute to increased expiratory muscle force and decreased duty cycle so that expiration acts like a Valsalva maneuver with inadequate time to recover during inspiration (Aliverti et al.
2002,
2005a; Iandelli et al.
2002). Furthermore, the decreased duty cycle magnifies the effect of high expiratory pressures when averaged over the whole respiratory cycle. Our present results show that EFL increased O
2 debt by an average 52% and led to hypoxemia in part due to hypercapnia. This supports our hypothesis that the reduction in cardiac output during EFL exercise decreases O
2 supply to working locomotor and respiratory muscles resulting in an increased O
2 debt. We conclude that the decreased cardiac output is important in limiting EFL exercise performance in healthy subjects.
EFL as a model for COPD
The experimental model used in this study was designed to simulate, in part, the flow-limitation commonly experienced by COPD patients during exercise. The pros and cons of this model have been previously extensively discussed (Aliverti et al.
2002; Iandelli et al.
2002). The model has demonstrated that exercise with EFL induces intolerable dyspnea, CO
2 retention, impaired exercise performance, expiratory muscle recruitment (Kayser et al.
1997), blood shifts from trunk extremities, a reduced duty cycle, arterial desaturation, and a decrease in cardiac output (Aliverti et al.
2005a).
In the present study, we confirmed many of these results and showed that the increased O
2 debt was accompanied by a reduction in
\({{\dot{V}}\hbox{O}_{2}}\) by 8% and a fall in SaO
2 by 4% at the end of EFL exercise, thus leading to a reduction in systemic O
2 delivery of ∼ 12%, in close agreement with the 15% reduction reported by Aliverti et al. (
2005a). It is reasonable to assume that the reduction in systemic O
2 delivery during EFL exercise would be associated with the progressive recruitment of fast-twitch fibers and hence the premature onset of the lactate threshold. The latter has been shown to be the case during exercise with EFL (Aliverti et al.
2005a). When exercise workloads exceed the lactate threshold, energy supplies are inadequate to meet demands. The resulting competition between working locomotor and respiratory muscles for the available energy supplies, regulated by autonomic reflex mechanisms (Harms et al.
1998), would be substantially worsened by the decrease in the available O
2 and should further increase the lactate production. It is therefore likely that the muscle and blood lactate levels (not measured in the present study) would be appreciably higher during EFL exercise and consequently, the lactate related metabolic cost could significantly contribute to the repayment of the O
2 debt in recovery from EFL exercise.
In addition to the reduction in systemic O
2 delivery, the present study shows that application of EFL during exercise significantly decreased minute ventilation compared to control exercise, causing hypercapnia. This confirms earlier results that show that a vicious circle is induced whereby increasing central ventilatory drive increases expiratory pressure which further reduces alveolar ventilation and cardiac output (Aliverti et al.
2002,
2005a; Iandelli et al.
2002). Furthermore, the observed elevated heart rate during EFL exercise possibly reflects a reduction in stroke volume secondary to the decrease in venous return. In the study by Stark-Leyva et al. (
2004), expiratory loading during exercise increased heart rate in an attempt to minimize the effects of the reduced stroke volume on cardiac output. Thus, the reduced cardiac output secondary to the high expiratory pressures would also be expected to contribute importantly to the greater oxygen debt that was measured after EFL exercise.
In summary, EFL exercise in healthy subjects reproduces many features of COPD including acute respiratory failure, a condition resembling cor pulmonale, dyspnea, and impairment of exercise performance. Furthermore, it has led to testable predictions, one of which is the rationale for this study and which to date have been proven to be accurate (Aliverti et al.
2004b,
2005a,
b).
Off-transient O2 kinetics
The increase in O
2 debt by 52% that we found during EFL exercise impacted, as predicted, on O
2 kinetics during recovery. Accordingly, the repayment of O
2 debt after EFL exercise started at a higher
\({{\dot{V}}\hbox{O}_{2}}\) compared to control and the off-transient time constant of the fundamental and slow
\({{\dot{V}}\hbox{O}_{2}}\) components were shorter after EFL exercise. Collectively, the findings describing the EFL off-transient O
2 kinetics reflect a more rapid replenishment of blood O
2 stores (fundamental component) and a faster repayment of O
2 tissue debt (slow component), both of which could result from the greater O
2 deficit during EFL exercise as opposed to control exercise. Indeed, if we considered that cardiac output during EFL exercise was lower than control and
\({{\dot{V}}\hbox{O}_{2}}\) was not significantly different between EFL and control, then it would be reasonable to expect that during exercise with EFL, that is known to decrease pulmonary blood flow (Aliverti et al.
2005a), the arterial to mixed venous blood O
2 difference would be larger and the mixed venous blood O
2 content would be lower. This notion was confirmed by our calculations of arterial to mixed venous blood O
2. When at the end of exercise EFL was removed, the sudden increase in cardiac output and in blood perfusing the lungs brought about a refilling of the O
2 stores of mixed venous blood; hence the sudden increase of
\({{\dot{V}}\hbox{O}_{2}}\) (marking the replenishment of the body’s deprived oxygen stores), a faster
\({{\dot{V}}\hbox{O}_{2}}\) kinetics and a larger O
2 debt in EFL (Table
5). The larger depletion of the inner oxygen stores is also suggested by the longer time constants of the on- and off-transient
\({{\dot{V}} {O}_{2}}\) response during EFL exercise (Table
3). Our calculations showed that approximately 30% of the O
2 debt difference between EFL and control exercise was due to the blood O
2 replenishment (Table
5) caused by the reduced cardiac output during EFL, whereas the rest was due to other possible mechanisms described below.
In line with the results of Cunningham et al. (
2000) and Ozyener et al. (
2001) describing O
2 kinetics after heavy exercise, the off-transient
\({{\dot{V}}\hbox{O}_{2}}\) data after EFL exercise were best fitted by a two component exponential function. The fundamental off-transient component after control exercise (40.6 s) was similar to that (∼ 33 s) described by Cunningham et al. (
2000) and Ozyener et al. (
2001) following very heavy exercise, lasting as in the present study for 6 min. On the other hand, the time constant of the fundamental component after EFL exercise (26.6 s) was significantly shorter than that of control exercise, thus confirming replenishment of the body’s deprived oxygen stores upon removal of EFL. In addition, the shorter time constant calculated after EFL is the result of fitting the data from higher starting points as evidenced by the significantly higher
a +
c values shown in Table
4 and Fig.
5c.
Furthermore, the time constant of the slow component after EFL exercise (1,020 s) was twofold longer than the one (460 s) described previously for very heavy exercise (Ozyener et al.
2001) possibly reflecting the additive effects of the EFL-induced reduction in systemic O
2 delivery on the repayment of tissue O
2 debt. Although at present the mechanism(s) of the
\({{\dot{V}}\hbox{O}_{2}}\) slow component is not fully understood, there are important factors that could influence the slow component after EFL exercise. These include the blood lactate concentration (Poole et al.
1994), the influence of the metabolic acidosis on the HbO
2 dissociation curve (Wasserman et al.
1991), the increased respiratory and cardiac muscle energy requirement associated with EFL exercise (Aaron et al.
1992; Harms et al.
1998), the progressive recruitment of type-II fibers (Coyle et al.
1992) and to a lesser extent the increased levels of circulating catecholamines (Gaesser et al.
1994) associated with the greater cardiovascular response during EFL exercise. Importantly, excessive expiratory muscle recruitment has been shown in patients with airflow limitation to increase the oxygen cost of breathing threefold (Aliverti et al.
2004b). Accordingly, it is reasonable to assume that the higher O
2 cost of breathing during EFL exercise would significantly enhance the O
2 dept as compared to exercise without EFL.
In the present study, we utilized a double-exponential function to describe the off-transient
\({{\dot{V}}\hbox{O}_{2}}\) kinetics not only for EFL exercise but also for control exercise [typically fitted by a mono-exponential function (Cunningham et al.
2000; Ozyener et al.
2001)], in order to allow adequate comparisons of relevant parameters of recovery for both exercise tests. Accordingly, the slow component observed after control exercise was not discernible in two subjects using the double-exponential function. This is in accordance with previously reported data by Cunnnigham et al. (
2000) who exercised healthy subjects at a similar work rate (100 W), yielding similar exercise
\({{\dot{V}}\hbox{O}_{2}}\) (1.7 l min
−1) as the one reached in the present study during control exercise. In conditions where exercise is sustained at a moderate intensity, as in the control test, the off-transient slow component is often not discernible such that
\({{\dot{V}}\hbox{O}_{2}}\) kinetics can retain first-order characteristics (Cunnnigham et al.
2000; Gerbino et al.
1996; Ozyener et al.
2001).
In conclusion, the results of the present study provide further evidence that expiratory flow limitation during exercise reduces systemic O2 delivery, enhances the O2 debt and leads to hypoxemia in part due to hypercapnia.