| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, and University of Texas Southwestern Medical Center-Dallas, Dallas, Texas; and 2Department of Comparative Bioscience, University of Wisconsin-Madison, Madison, Wisconsin
Submitted 21 July 2007 ; accepted in final form 6 November 2007
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
E)-CO2 production (CO2) relationship, 
E/CO2]. On the basis of animal studies, it has been proposed that a central neural mechanism links the exercise ventilatory response to the resting ventilatory drive without need for changes in chemoreceptor feedback from rest to exercise, a mechanism referred to as short-term modulation (STM). We tested the hypothesis that STM is elicited by increased resting ventilatory drive associated with added external dead space (DS) in humans. Twelve young men were studied in control conditions and with added DS (200, 400, and 600 ml; randomized) at rest and during mild-to-moderate cycle exercise. E/CO2 increased progressively as DS volume increased (P < 0.0001). While resting end-tidal PCO2 (PETCO2) increased with DS, the change in PETCO2 from rest to exercise was not increased, indicating that increased chemoreceptor feedback from rest to exercise cannot account for the greater exercise ventilatory response. We conclude that STM of the exercise ventilatory response is induced in young men when resting ventilatory drive is increased with external DS, confirming the existence of STM in humans. exercise hyperpnea; respiratory control; hypercapnia
A) in direct proportion to increased metabolic CO2 production (CO2). Arterial PO2 and [H+] also remain constant, indicating that the ventilatory response to moderate exercise is not driven by feedback from chemical stimuli (6, 9). Our understanding of the exercise ventilatory response, i.e., the close matching between ventilation (E) and CO2, has changed little since Grodins' early analysis (9), although many theories have been proposed (for review see Ref. 10). The present study is not concerned with how the exercise ventilatory response is initiated but rather with how this response is modulated when resting conditions are altered.
Under conditions that chronically alter resting arterial PCO2 (PaCO2), relative arterial isocapnia is still maintained during exercise (6). For example, when resting PaCO2 is raised (e.g., carotid body denervation or metabolic alkalosis) or lowered (e.g., metabolic acidosis, increased progesterone levels, or serotonin depletion), PaCO2 during exercise is regulated with the same precision in relation to its new resting level (for review, see Ref. 6). Such constant relative regulation of blood gas homeostasis requires active ventilatory control mechanisms that adapt the exercise ventilatory response to the prevailing physiological conditions. The A-PaCO2 relationship, as defined by the alveolar gas equation, is hyperbolic. In exercise, the curve is shifted upward and is steeper than that at rest [see Fig. 1 of Bennett and Fordyce (3)]. Because of the difference in steepness between the curves at rest and during exercise, the slope of the exercise ventilatory response must change considerably to maintain isocapnia during exercise when resting PaCO2 has been altered. If the resting PaCO2 is lowered (i.e., increased resting ventilatory drive), then maintenance of PaCO2 at its new level (i.e., isocapnic exercise ventilatory response) requires a greater increase in E at the same level of exercise; in other words, the slope of the E-CO2 relationship would need to be increased by active mechanisms of ventilatory control (3). Conversely, if resting PaCO2 is raised (i.e., decreased resting ventilatory drive), a smaller increase in E is required to maintain isocapnia; in other words the slope of the E-CO2 relationship must be decreased by active neural control mechanisms. If resting ventilatory drive (and PaCO2) was altered without subsequent changes in the exercise ventilatory response, relative hypercapnia or hypocapnia would develop with respect to resting PaCO2 (3, 21, 23). Because such adjustments are found with a wide range of perturbations to resting ventilation, a common mechanism has been proposed to link resting ventilatory drive (rather than resting PaCO2 per se) with the exercise ventilatory response (21).
|
CO2 (but not A) to maintain isocapnia from rest to exercise (18). Such an increase requires greater activation of the respiratory muscles; in other words, it requires active changes in neural activation from respiratory motor neurons. Modulation of the exercise ventilatory response elicited by adding external dead space has been studied extensively in the goat model (2, 18, 21). On this basis, it was concluded that the exercise ventilatory response is more tightly associated with resting ventilatory drive than resting PaCO2 per se. Dead space has advantages over other experimental methods of altering resting PaCO2 in that the change in baseline PaCO2 is acute, lasting only as long as the dead space is included in the breathing circuit, and the effects are localized to the control of breathing, as opposed to the whole body effects of inducing metabolic acidosis or alkalosis, or changing hormone or neurotransmitter levels. The mechanism whereby added external dead space increases the exercise ventilatory response is independent of chemoreceptor feedback from rest to exercise in goats (18). It was proposed that dead space, and other experimental treatments that alter resting ventilatory drive, modulate the exercise ventilatory response via a common mechanism linking the exercise ventilatory response with resting ventilatory drive. This mechanism has been referred to as short-term modulation (STM) of the exercise ventilatory response since the exercise ventilatory response was reversibly augmented within a single trial of exercise (2). We have adopted the same terminology in referring to this mechanism, for consistency with the animal work on which our study is based.
The purpose of the present study was to translate the work establishing STM in an animal model (i.e., goats), employing a comparable protocol in young, healthy human subjects. While other investigators have described the effects of dead space on the exercise ventilatory response in humans, these studies did not explicitly or prospectively address the presence or mechanism of STM (13, 24, 28). Our purpose was not to examine the effects of dead space per se on the exercise ventilatory response, but to determine if added dead space modulates the exercise ventilatory response in a predictable manner similar to the goat studies (2, 18). Confirming the existence of STM in humans establishes the necessary background for future studies concerning the mechanism and functional significance of STM in humans, particularly its potential significance in the normal ageing process and processes related to lung disease.
We hypothesized that in young human male subjects: 1) the exercise ventilatory response would be increased by added external dead space; and 2) this modulation would be independent of chemoreceptor feedback from rest to exercise, thereby confirming the existence of STM. Any observed increase in chemoreceptor stimuli from rest to exercise would have suggested that increases in the exercise ventilatory response were not solely due to STM, but could be explained (at least in part) by classical chemoreceptor feedback (4, 18). We used end-tidal PCO2 (PETCO2) as an indicator of PaCO2 in this study. Although PETCO2 increases during exercise in humans (14, 25) while PaCO2 remains within 1–2 Torr of the resting level, we examined the change in PETCO2 from rest to exercise. The relative nature of this index is expected to reasonably reflect changes in PaCO2 (vs. absolute levels). Some of the results of this study have been reported previously, in preliminary form (31).
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
Male volunteers were recruited from local advertisements. All subjects were current nonsmokers and had no history of cardiovascular disease, diabetes, or asthma. They were either sedentary or participated in regular exercise but were not in training for any specific event. The study conformed to the standards set by the Declaration of Helsinki and was approved by our Institutional Review Board. Subjects gave their written informed consent to participate. Subjects attended the laboratory for three separate visits and were asked to refrain from eating or consuming caffeine for at least 2 h before each visit. On the first occasion they undertook pulmonary function testing and were familiarized with exercise on the cycle ergometer. On the second visit they performed an incremental cycle exercise test to exhaustion, and on the third they undertook the STM protocol, as detailed below.
Pulmonary Function Testing
Standard measurements of spirometry, lung volume, and diffusing capacity were performed for each subject (model V62W body plethysmograph, Viasys Healthcare, Yorba Linda, CA) according to American Thoracic Society guidelines (1). Predicted values were based on norms by Knudson et al. (15, 16), Goldman and Becklake (8), and Burrows et al. (5).
Incremental Exercise Testing
Incremental exercise was performed on an electromagnetically braked cycle ergometer. Subjects were seated on the ergometer at rest for 6 min, followed by 6 min constant-load cycling at 30 W, after which the work rate was increased by 30 W every 60 s until the subject could no longer maintain a pedal rate of 50 rpm. Subjects were verbally encouraged to continue to exhaustion. At this point, work rate was reduced to 30 W, and subjects pedaled slowly for 5 min of recovery. Heart rate (HR) was monitored throughout by five-lead ECG, and arterial O2 saturation (SaO2) was monitored by pulse oximetry, using a forehead probe (Nellcor, Pleasanton, CA).
STM Protocol
Subjects undertook five successive exercise trials on the cycle ergometer, each lasting 24 min, separated by 20 min of rest. Each trial consisted of 6 min of rest followed by 6 min of constant-load exercise at each of three levels: 10, 30, and 50 W (order not randomized). For all subjects, the first and last trials were controls with no added dead space. For each of the middle three trials, an external dead space, consisting of a length of wide-bore reinforced tubing with a volume of 200 ml, 400 ml, or 600 ml, was added to the breathing circuit, in a randomized order. Subjects were not explicitly told which dead space volume was used in each trial, but the addition of the tubing to the mouthpiece assembly was not shielded from their view. The order of the three dead space trials was randomly assigned such that each of the six possible permutations was undertaken by two subjects.
Ventilatory and Gas Exchange Measurements
PETCO2 was manually recorded every 15 s from a capnograph (Poet TE, Criticare Systems, Waukesha, WI), which was checked against a calibration gas with a known fraction of CO2 before each testing session. Respiratory frequency (Rf) was recorded on a custom-built computerized breath-by-breath system and averaged over 20-s intervals. Additionally, expired gas was collected during the 3rd to 5th minute at rest and during the 4th and 5th minutes at each level of exercise, in 200-liter PVC Douglas bags (Harvard Apparatus, Holliston, MA). Inspired and expired fractions of O2, CO2, and N2 were determined by mass spectrometry (Perkin-Elmer 1100, Waltham, MA) and O2 uptake (O2) and CO2 were calculated using standard equations over the period of expired gas collection. Expired minute ventilation (E, BTPS) was measured with a Tissot spirometer. VT was calculated as E/Rf. Except for PETCO2 and Rf, all ventilatory and gas exchange data presented were obtained from the expired gas collections. Values for PETCO2 and Rf were averaged over the same periods as the expired gas collections. PaCO2 was estimated from measurements of PETCO2 and VT (in liters) using the equation described by Jones and colleagues (14).
Data Analysis
For the incremental exercise test, O2 calculated from the expired gas collection at the final work rate was taken as peak O2 (O2peak). For the STM protocol, variables were expressed both as absolute values at rest and each work rate and as the change from rest to each work rate, i.e., relative to rest (denoted by ). The exercise ventilatory response was defined as the slope of the E-CO2 relationship (E/CO2). Figure 1 illustrates this calculation for the exercise trial with 200 ml added dead space. Figure 1, top, shows the E-CO2 relationship at each work rate for individual subjects; Fig. 1, bottom, shows how slope was calculated. The value for slope given in the bottom panel is the mean of the individual responses in the corresponding top panel. E and CO2 were measured in liters per minute; hence, the slope of the E-CO2 relationship is dimensionless.
For the STM protocol, differences between mean values were tested using a two-way repeated measures ANOVA with activity level (rest and 3 levels of exercise) and dead space level (2 controls and 3 levels of added dead space) as within-subject factors. The Tukey test was used for post hoc multiple comparisons analysis. The effect of each dead space volume on ventilatory drive at rest was determined by comparing resting variables from the trials with 200, 400, and 600 ml added dead space with those from the first control trial, using Student's paired t-tests. P values were adjusted using the Bonferroni correction for multiple comparisons. In addition to this main analysis, the two control trials were compared separately, using the same repeated measures ANOVA, to test whether there were any differences between air-breathing responses before and after the three exercise trials with dead space.
Any effect of the order in which the exercise trials were undertaken was tested using a one-way ANOVA on the randomization order (6 permutations, each undertaken by 2 subjects), by exercise level and dead space level. For the slope of the exercise ventilatory response, this gave 15 separate ANOVAs (3 levels of exercise by 5 levels of dead space, including the 2 control trials). Only one of these (400 ml dead space at 30 W) showed a significant effect of order on slope (P < 0.05). It is not obvious from our data why this combination of dead space and exercise level would be different from the other 14 combinations; we therefore concluded that there was no systematic effect of test order.
All statistical analyses were undertaken using SAS version 9.1 (SAS Institute, Cary, NC), and a P value of <0.05 was taken as statistically significant. Data are presented as means ± SD.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
Twelve subjects completed the study. Their individual physical characteristics are given in Table 1, along with values for O2peak from the incremental exercise test, and selected pulmonary function test results. Pulmonary function was within normal ranges in all subjects, based on age and race. Exercise capacity was normal; O2peak was 97 ± 16% of the predicted value (12), and maximal HR was 91 ± 4% of the predicted value (11). For the most part, fitness level was within the normal range according to American Heart Association standards (7): O2peak was 34.6 ± 4.5 ml·kg–1·min–1. At peak O2, E was 110.1 ± 18.4 l/min, equivalent to 67 ± 10% of maximal voluntary ventilation (MVV; the maximal amount of air that can be moved in and out of the lungs in 60 s, estimated from 10- to 12-s measurement).
|
Exercise level.
Oxygen uptake (expressed as a percent of O2peak) averaged 
20% at 10 W, 27% at 30 W, and 35% at 50 W. The range of values across the five exercise trials for 50 W (26–49%) falls below the average predicted anaerobic threshold for men in this age group, although there is some overlap with the lower 95% confidence limit (29). Since O2 (%O2peak) at a given work rate did not differ between the five exercise trials, any effect of reaching the anaerobic threshold would have been constant between the control trials and those with added dead space.
Resting ventilatory drive.
At rest, PETCO2 increased progressively with the addition of increasing dead space volume, from a baseline value of 40.7 ± 4.7 Torr (Table 2), but only reached a significant difference from control 1 with 600 ml added dead space (corrected P < 0.01). Resting E also increased progressively with the addition of dead space and was significantly higher than baseline with each dead space load (12.0 ± 2.6 l/min in control 1 vs. 15.2 ± 2.8 l/min with 200 ml, 17.8 ± 3.5 l/min with 400 ml, and 19.4 ± 5.1 l/min with 600 ml dead space; corrected P < 0.01). The elevation in resting E was mainly due to an increase in VT, which was significantly higher with 400 and 600 ml added dead space than in control 1 (corrected P < 0.05; VT was increased with 200 ml but not significantly; Rf was not different from control 1 with any level of added dead space). These results indicate that resting ventilatory drive was significantly elevated with all three levels of added dead space.
|
PETCO2 during the trials with added dead space was not increased compared with control 1 (P < 0.01), indicating that CO2 was not retained and hence that chemoreceptor feedback was not increased from rest to exercise.
|
|
Compared with control 1, the exercise ventilatory response (slope, E/CO2) increased progressively with increasing dead space volume (P < 0.0001; Table 3, Fig. 2) but decreased progressively as work rate increased (P < 0.0001). ANOVA revealed a significant interaction between the effects of dead space volume and work rate on slope (P < 0.01). This can be seen more clearly in Fig. 3, where data from Fig. 2 have been plotted as a line graph. If there was no interaction we would expect the lines on this graph to be parallel. (For clarity, error bars and data from control 2 are not shown in Fig. 3; for values, see Table 3). The dead space volume appeared to have a greater effect on the slope of the exercise ventilatory response than the work rate.
|
|
E from rest to exercise (E) compared with control 1 (P < 0.02), due to a greater frequency response to exercise in control 2 (P < 0.01), with no difference between the two trials in the VT response (see Table 3). In addition, PETCO2 was significantly lower (P < 0.01) in control 2, which suggested that the subjects were hyperventilating modestly during the second control trial. To determine whether there was any difference in the resting ventilatory drive between the two control trials, resting variables were compared using Student's paired t-tests (with Bonferroni correction). There were no significant differences between the two trials for E, CO2, or PETCO2, confirming that there was no meaningful difference in resting ventilatory drive. |
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
Previous Studies
Studies in animal models. Our results are very similar to those described in goats. Mitchell (18) examined the ventilatory response to treadmill exercise with 200 and 600 ml added dead space and found that the magnitude of the increase in slope of the response depended on both the dead space volume and the exercise intensity. We observed increases in slope within a range overlapping that reported in goats (13–75% in our study vs. 39–178% in the goat study), and a reduction in the increase in slope as exercise intensity increased. In the goat study, an increase in PaCO2 was observed at the highest work rate with the largest dead space volume, indicating a limit in the capacity for STM; STM could not augment the gain of the exercise ventilatory response sufficiently to maintain an isocapnic response, and PaCO2 increased from rest to exercise. We did not observe a greater increase in PETCO2 from rest to exercise at any level of dead space in our study (compared with control), most likely because our range of dead space volumes was smaller than that used in the goats when expressed relative to body size (the goats weighed 39–51 kg).
The exercise ventilatory response has also been studied in goats under different experimental conditions which chronically altered resting PaCO2. Mitchell and colleagues lowered resting PaCO2 in goats by reducing central serotonin levels (via administration of the tryptophan hydroxylase inhibitor p-chlorophenylalanine) and found that the gain of the exercise ventilatory response was significantly increased, such that PaCO2 was maintained at its new resting level (22). In the converse situation, resting PaCO2 was raised via bilateral carotid body denervation, and the exercise ventilatory response was significantly reduced, again resulting in regulation of PaCO2 at its new resting level (21). The constant relative regulation of PaCO2 under these different experimental conditions suggests an active (and common) mechanism (i.e., STM) that increases or decreases the exercise ventilatory response inversely with changes in resting PaCO2 or directly in relation to changes in resting ventilatory drive. Experiments with added external dead space, where both resting PaCO2 and ventilation increase acutely, suggest that this mechanism matches the exercise ventilatory response to the level of resting ventilatory drive, rather than to resting PaCO2 per se.
Studies in humans. Further data supporting our results can be found in the literature for humans. Oren and co-workers (23) manipulated the acid-base balance to raise (metabolic alkalosis) or lower (metabolic acidosis) resting PaCO2 and reported that the new levels of resting PaCO2 resulting from the chronic acid-base changes were maintained during moderate exercise. Compared with the baseline response, the ventilatory response to the same level of exercise was increased under acidosis (i.e., increased resting ventilatory drive) and reduced under alkalosis (i.e., decreased resting ventilatory drive). A similar finding was reported by Skatrud and colleagues (26), who lowered the level of resting PaCO2 (i.e., increased resting ventilatory drive) in a group of men by raising the level of progesterone. The ventilatory response to moderate exercise was increased (26) and the new lower level of resting PaCO2 was maintained (6). These studies suggest that STM may also operate in humans to adjust the exercise ventilatory response when resting ventilatory drive is chronically altered.
Regarding acute changes in the level of resting ventilatory drive in humans, a number of studies have examined the exercise ventilatory response with added external dead space (13, 24, 28). Jones and colleagues (13) reported that during exercise with added dead space ventilation increased, although this increase was "insufficient to restore the PCO2 to normal" (13). However, with the larger dead space volume used in their studies (1,400 ml), it is likely that the capacity for STM had been exceeded in these subjects. Furthermore, since neither resting PETCO2 values nor the slope of the exercise ventilatory response are shown, it is difficult to interpret these results.
Ward and Whipp (28) examined the regulation of estimated alveolar PCO2 during exercise with a range of added external dead space volumes. They reported that "it was only at the largest dead space volumes that ventilatory inadequacy could actually be discerned," which indicates that the ventilatory response may have been augmented sufficiently to maintain alveolar ventilation and isocapnia up to this level of dead space (1,000 ml), as is shown in Fig. 4 of their paper. Furthermore, their data show that the slope of the E-CO2 relationship increased as dead space volume increased, suggestive of STM; however, there was some inconsistency in response between the three subjects studied, and not all subjects undertook exercise with the higher dead space volumes. The authors did not seek to address the neural mechanism whereby the E-CO2 slope was altered, but mainly focused on gas exchange.
Poon (24) reported a substantial increase in resting PaCO2 in the presence of 1,100 ml added dead space in healthy human subjects and found that isocapnia was maintained during mild exercise, accompanied by a significant increase in slope of the exercise ventilatory response of 57% compared with control. This apparent demonstration of STM is within the range of increases in slope observed in the present study. Similar to the goat study (18), Poon observed that the exercise ventilatory response was not augmented sufficiently to prevent PaCO2 from rising at higher work rates. We did not observe a similar limitation in our study, probably because we used smaller dead space volumes. Poon (24) rejected the model proposed by Mitchell et al. (21) to explain the increase in slope and instead suggested that within-breath oscillations of PaCO2 may constitute a signal during exercise, which is heightened by dead space, resulting in increased ventilatory drive. In addition, Poon (24) postulated that his observations could be explained by an optimization model of the respiratory controller. However, since similar changes in the slope of the exercise ventilatory response have been observed in humans under experimental conditions expected to dampen breath-by-breath PaCO2 oscillations (23, 26), or in goats without intact carotid body chemoreceptors [the putative sensor of PaCO2 oscillations (21)], it seems more likely that STM in humans relies on spinal serotonergic mechanisms similar to STM in goats (19).
Summary. Studies in animals and humans have shown that the exercise ventilatory response is adjusted in the face of both chronic and acute changes in the level of resting ventilatory drive, such that the exercise ventilatory response remains isocapnic. The present study has confirmed and extended the findings of other investigators who described the effects of dead space on the exercise ventilatory response; we have used a larger group of healthy subjects and avoided any possible confounding effects of age-related changes in lung function (24) by using only young subjects. We have observed that the exercise ventilatory response is modulated in a predictable manner, via STM (2, 18), and postulate that similar underlying neural mechanisms are likely in both species.
Significance/Interpretation
Modulation of the exercise ventilatory response with changes in resting ventilatory drive may represent an important homeostatic mechanism designed to prevent the relative respiratory acidosis or alkalosis that would result if the slope of the response had not been altered. The presence of STM demonstrates the ability of the ventilatory control system to adapt and adjust to a variety of conditions that cause a change in the resting ventilatory drive, to maintain a normal exercise ventilatory response. In addition to experimental conditions imposed in the laboratory, this would allow the ventilatory control system to compensate for physiological changes in resting ventilatory drive, such as may occur when wearing occupational breathing apparatus, during pregnancy, during acute lung infections, or with the normal deterioration of gas exchange experienced during ageing. STM may also confer the ability to maintain homeostasis of PaCO2 during exercise in pathophysiological conditions, such as obesity and lung disease, although there appears to be a limit to how much the exercise ventilatory response can be modified within the time scale of STM. A longer-lasting modulation of the exercise ventilatory response has been demonstrated in goats (17) and in young men (30) following repeated trials of exercise paired with added dead space or inhaled CO2.
Possible Mechanism
On the basis of their work in goats, Mitchell and colleagues have proposed the following neural mechanism to explain STM of the exercise ventilatory response: the feedforward exercise stimulus activates integrating premotor neurons in the brain stem, which provide descending central respiratory drive to spinal respiratory motor neurons, thus activating respiratory muscle contraction and stimulating ventilation. Experimental treatments that elicit STM by increasing resting ventilatory drive are proposed to co-activate brain stem raphe serotonergic neurons that project to the ventral spinal cord, increasing serotonin release, specifically in the vicinity of respiratory motor neurons (see Ref. 19). Serotonin receptor activation on respiratory motor neurons would increase their excitability, thereby amplifying the translation of descending respiratory drive from brain stem respiratory premotor neurons into respiratory motor neuron activity. This would result in greater ventilation and hence increase the slope of the relationship between ventilation and metabolic CO2 production, i.e., would elicit STM. Indeed, in goats, STM with added dead space is serotonin dependent (2) and requires the activation of serotonin receptors located in the spinal cord. It remains to be confirmed that STM in humans involves a similar serotonergic mechanism.
Limitations of this Study
Determination of isocapnia.
STM was determined as an increase in slope of the E-CO2 relationship with added dead space vs. control, confirmed by the maintenance of isocapnia from rest to exercise. Since we did not take arterial blood samples, PETCO2 was used throughout the study as an indicator of PaCO2. It has been established that at rest PETCO2 is a reasonable estimate for PaCO2, while during exercise, PETCO2 increases above PaCO2 by an amount that varies depending on CO2 and Rf (14, 25). Comparing different methods for estimating PaCO2 with actual arterial values, Robbins and co-workers (25) found the equation described by Jones and colleagues (14) to be the most accurate method. We used the Jones equation to estimate PaCO2; however, the same patterns were observed as for PETCO2, and hence we decided not to present these values. Although PETCO2 may under- or overestimate the absolute value of PaCO2, it is the value during exercise relative to its resting level (i.e., the change from rest to exercise) that defines whether the response is isocapnic or whether CO2 is retained. In this case, we believe that measuring the change in PETCO2 from rest to exercise was sufficiently accurate. We did not believe the potential benefit of introducing an arterial line would have outweighed the risk imposed on the subjects.
Volume of added dead space.
Using the same absolute dead space volumes as in the goat studies meant that our volumes were relatively smaller, since our human subjects were larger than the goats (85 kg vs. 50 kg), which may imply that we did not push our subjects as hard. This difference can be estimated from the dead space volume/VT ratios; with 600 ml dead space, the ratio was 0.73 in the present study vs. 0.86 in the earlier study of Mitchell (18). The limitation of using smaller dead space loads is that we do not have information regarding the upper limit of STM expression. However, the advantage is that we should be able to use the same small dead space volumes in future studies of aged or diseased patients where the capacity for STM may be more modest and the limit may be lower.
Control trials.
It is difficult to explain our finding that the slope of the exercise ventilatory response was increased in the second control trial compared with the first. However, we do not believe the increase in slope represents STM, and hence believe this is different from the increase observed with added dead space for two reasons: 1) resting levels of PaCO2 and E were not increased in control 2 compared with control 1; and 2) the increased ventilatory response during control 2 was due to a greater frequency response to exercise, with no change in the response of VT. Since the subjects were aware that control 2 was the last trial of a rather long protocol, we suggest that the modest hyperventilation was due to behavioral effects resulting from their anticipation of completing the protocol.
Effect of order. We found that the order in which the DS trials were undertaken apparently had a significant effect on the slope of the exercise ventilatory response with 400 ml DS at 30 W. Since this was the only significant result of 15 ANOVAs to test the effect of order, it may be a random finding; had the effect been significant with 400 ml DS at 10 W and 50 W this would suggest a real difference between subjects, depending on the order in which they undertook the trials. However, this was not the case, and we do not believe this finding affects the results of the study.
Conclusion
In conclusion, when the level of resting ventilatory drive is raised acutely by the addition of external dead space, the exercise ventilatory response in humans is augmented within a single exercise trial via a mechanism independent of chemoreceptor feedback from rest to exercise. This mechanism is referred to here, and in the animal studies on which this study is based, as short-term modulation, or STM, of the exercise ventilatory response. Confirming the existence of STM in healthy young men is the first step in establishing the concept that the exercise ventilatory response is changeable and can be adapted to the prevailing conditions. STM may be an important adaptive mechanism in maintaining the homeostatic regulation of PaCO2 during exercise under physiological and pathophysiological conditions that compromise resting blood gas homeostasis. Further studies are required to confirm the relevance of STM under such conditions, and whether STM in humans involves a similar serotonergic mechanism to that proposed in goats.
|
GRANTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
|
FOOTNOTES |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
CO2 relationship during exercise in goats: role of carotid bodies. J Appl Physiol 57: 1894–1900, 1984.This article has been cited by other articles:
|
|
 |
|
  C.-S. Poon The classic potentiation of exercise ventilatory response by increased dead space in humans is more than short-term modulation J Appl Physiol, July 1, 2008; 105(1): 390 - 390. [Full Text] [PDF]
|
|
|
|
|
|
H. E. Wood, G. S. Mitchell, and T. G. Babb Reply to Dr. Poon J Appl Physiol, July 1, 2008; 105(1): 391 - 391. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
