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J Appl Physiol 99: 1012-1018, 2005. First published April 28, 2005; doi:10.1152/japplphysiol.00475.2004
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Role of arterial hypoxemia and pulmonary mechanics in exercise limitation in adults with cystic fibrosis

Edward F. McKone, Sinead C. Barry, Muiris X. FitzGerald, and Charles G. Gallagher

Department of Respiratory Medicine and National Referral Center for Adult Cystic Fibrosis, St. Vincent's University Hospital, Dublin, Ireland

Submitted 4 May 2004 ; accepted in final form 11 April 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We tested the hypothesis that maximal exercise performance in adults with cystic fibrosis is limited by arterial hypoxemia. In study 1, patients completed two maximal exercise tests, a control and a test with 400 ml of added dead space. Maximal O2 consumption was significantly lower in the added dead space study vs. control (1.04 ± 0.15 vs. 1.20 ± 0.11 l/min; P < 0.05), with no difference in peak ventilation. There was significant O2 desaturation during exercise that was equal in both control and added dead space studies. The decrease in maximal O2 consumption with added dead space suggests that maximal exercise in cystic fibrosis is limited by respiratory factors. We subsequently examined whether pulmonary mechanics or arterial hypoxemia limits maximal exercise performance. In study 2, patients completed two maximal exercise tests, a control and a test with 400 ml of added dead space while also breathing 38% O2. Added dead space was used to overcome the suppressive effects of hyperoxia on minute ventilation. Maximal O2 consumption was significantly higher with added dead space and 38% O2 vs. control (1.62 ± 0.16 vs. 1.43 ± 0.14 l/min; P < 0.05). Peak ventilation and O2 saturation were significantly greater in the added dead space and 38% O2 test vs. control. The increase in maximal O2 consumption and peak ventilation with added dead space and 38% O2 suggests that maximal exercise in cystic fibrosis is limited by arterial hypoxemia.

oxygen; treatment; pulmonary mechanics; gas exchange

PATIENTS WITH CYSTIC FIBROSIS (CF) often have reduced maximal exercise capacity (6, 9, 10, 16, 22, 28), which is an important predictor of mortality (33, 35). Although various abnormalities have been described during exercise in adults with CF (6, 9, 16, 22, 27, 28), it is not clear how much they contribute to exercise limitation. Factors that may limit exercise in CF patients include abnormal pulmonary function (6, 16, 22, 28) and impaired nutrition (9, 27, 28), although recently a number of studies have suggested that limb muscle dysfunction, rather than respiratory function, may be a major contributor (13, 14, 23).

We hypothesized that maximal exercise is limited by respiratory function. It is not currently known whether respiratory function limits maximal exercise in CF patients, although it has been suggested that ventilatory limitation and arterial hypoxemia may play a role (6, 16, 22, 28, 30). The assumption that ventilatory limitation occurs during maximal exercise has been based on the observation that CF patients have an elevated ratio of peak minute ventilation (E) to maximal voluntary ventilation (MVV) at end exercise (16, 22, 28), whereas arterial hypoxemia has been implicated because some CF patients improve their maximal and submaximal exercise capacity while breathing supplemental O2 (29, 31).

These observations do not confirm whether ventilatory limitation or arterial hypoxemia limits maximal exercise capacity in CF patients. An elevated E-to-MVV ratio at end exercise is not a reliable measure of ventilatory limitation (15, 20), with many CF patients reaching a peak E that exceeds their MVV during exercise (6, 16, 28). Also, supplemental O2 may improve maximal exercise capacity purely by reducing hypoxic drive to breathe. In patients with ventilatory limitation, this reduction in E during exercise increases the time taken to reach maximum ventilatory capacity and so improves exercise duration. This mechanism has been implicated in the increased performance during exercise with supplemental O2 observed in patients with chronic airflow limitation (CAL) and interstitial lung disease (ILD) (18, 25, 37, 40).

The purpose of this study is to test whether maximal exercise in CF patients is limited by respiratory factors (either pulmonary mechanics and/or gas exchange). To determine whether respiratory factors limit maximal exercise in CF, we selectively stressed the respiratory system during exercise using added dead space (VD) (26, 32). If added VD resulted in reduced maximal exercise performance, we could conclude that maximal exercise capacity in CF patients was limited by respiratory factors. We subsequently examined the respective role of ventilatory limitation and arterial hypoxemia during exercise using a combination of supplemental O2 and added VD (18). Supplemental O2 was used to prevent arterial desaturation during exercise. Because supplemental O2 could result in increased exercise capacity by altering the ventilatory response to exercise, added VD was used to overcome the suppressive effects of hyperoxia on E (18, 25, 37, 40). If CF patients were able to increase both their maximal exercise capacity and peak E with supplemental O2 and added VD, this would suggest that maximal exercise was limited by arterial hypoxemia. Alternatively, if there was no improvement in maximal exercise performance or peak E with supplemental O2 and added VD, we could conclude that ventilatory limitation was the main factor limiting exercise performance in CF patients.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Patients were recruited from the clinics in the National Referral Center for Adult Cystic Fibrosis, St. Vincent's University Hospital. All patients were diagnosed with CF based on established criteria (39). The study was approved by the Ethics Committee of St. Vincent's University Hospital. All patients gave informed consent to the procedures.

Pulmonary function testing was carried out on each patient before and after each exercise test using recommended techniques (1) and predicted normal values (47) were used to calculate percentage predicted values.

All exercise testing was performed on an electrically braked cycle ergometer (Excalibur, Lode, Groningen, The Netherlands). Each exercise test was a maximal test carried out until exhaustion. Our laboratory previously showed that maximal exercise testing in this population is reproducible with no learning effect (30). Exercise was performed at the same time of day on each occasion. Subjects were asked to avoid strenuous activity for at least 24 h before exercise testing as well as food or caffeinated drinks in the preceding 2 h. All patients were instructed to take all of their maintenance medications as usual.

For the exercise tests, after mounting the cycle ergometer, each patient put on a nose clip, inserted the mouthpiece, and breathed comfortably for at least 6 min (see below). Baseline measurements were then taken over 2 min. The initial exercise workload was 15 W and was increased by 15 W/min in a ramp fashion until exhaustion. With the use of speedometer feedback, each subject chose the pedaling rate within a range of 50–70 rpm. All subjects were instructed in an identical manner by the same operator for all exercise studies. The subjects were told that they should continue to exercise until they could exercise no more. No other type of encouragement was offered and no communication was made with the subjects during the testing to ensure consistency of the protocol.

Electrocardiographic leads attached to the chest enabled continuous monitoring of the heart rate (HR) and electrocardiogram. Arterial O2 saturation (SaO2) was monitored by pulse oximetry (SAT-TRAK, Sensor Medics, Yorba Linda, CA). The nonrebreathing valve was connected via wide-bore tubing to a 2.6-liter mixing chamber with a heated wire flow sensor at the entrance to the mixing chamber (Mass Flow Meter, Sensor Medics). Respired gases were sampled by rapidly responding O2 (paramagnetic) and CO2 (infrared) analyzers. Respiratory and ventilatory data were averaged over a 20-s time period to give measured variables. All equipment was calibrated before each exercise study using calibration syringes and precision O2 and CO2 gas mixtures. All signals were displayed on a computer screen in real time during the exercise test. Data were also stored on computer hard disk for later analysis.

Study 1.   Patients underwent two exercise tests over a 7-day period with each test separated by a minimum of 48 h. The order of testing was randomized. Control and added VD exercise testing were identical except for the addition of 400 ml of VD inserted between the mouthpiece and the Hans Rudolph valve, using a methodology described by McParland et al. (32) and Marciniuk et al. (26), in the added VD study. A volume of 400 ml of added VD was chosen since this volume has been shown to be sufficient to significantly increase E during exercise in patients with moderate to severe lung disease (18, 26).

Study 2.   Patients underwent two exercise tests over a 7-day period with each test separated by a minimum of 48 h. The order of testing was also randomized. Control test was carried out with the patient breathing room air with no added VD. The intervention test (added VD/O2 study) was carried out with the patients breathing supplemental O2 (BOC gases: 38% O2-72% N2) with 400 ml of added VD between the mouthpiece and the Hans Rudolph valve, as described by Harris-eze et al. (18).

Because O2 consumption (O2) was measured while breathing supplemental O2, a number of additional precautions were taken to ensure that the respired gas measurements were accurate (38, 46). Before exercise with supplemental O2, the equipment was calibrated to ensure accurate measurement of the inspired gas concentrations (BOC gases: 38% O2-72% N2). Each subject put on a nose clip and breathed through a Hans Rudolph valve with the inspired limb connected to a 1,000-liter Douglas bag filled with the humidified hyperoxic gas mixture. The patients then rested, comfortably breathing for at least 6 min to ensure that their lungs were equilibrated with the hyperoxic gas mixture. Baseline measurements were recorded until there was <10% variability between repeated measurements of O2 over a 2-min period (i.e., steady-state O2 was reached). Inspired O2 fraction was measured every minute during exercise through a sampling port in the Douglas bag.

Patients in each study were blinded to the content of the inhaled gas and to the use of external VD, and, to ensure consistency of the protocol, room air was humidified and administered during the control study in an identical way to the O2 in the supplemental O2 study.

Data analyses. E, tidal volume (VT), respiratory frequency, HR, O2, and CO2 output were measured every 20 s using standard formula (21, 45). End-tidal CO2 was measured every minute through a sampling port at the patient's mouth. E and VT were expressed at BTPS and O2 and CO2 output were expressed at STPD. Predicted peak O2 during exercise was calculated as (21)  

where height (ht) is in meters and S is a factor taking account of gender (S = 0 for men and 1 for women). Predicted peak HR was calculated as (21)

MVV was predicted using the equation (8) forced expiratory volume in 1 s x 40.

The magnitude of dyspnea was assessed using the Borg scale in response to the question "How breathless do you feel?" with the subject pointing to the appropriate number on the scale. Leg discomfort was assessed using the Borg scale as above in response to the question "How much leg discomfort do you feel?" Each patient was also asked the reason for stopping exercise immediately after each exercise test.

Statistical significance of group mean data at end exercise from the two experimental days was determined by paired t-testing. Group mean data at matched submaximal work rates were compared by ANOVA for repeated measures (11). Analysis of the Borg scale was performed using Wilcoxon's signed rank test. The results are shown as means ± SE. Linear regression was used to determine an association between outcomes of interest and various physiological measures during exercise. P < 0.05 was considered significant.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Characteristics of the population in each study group are shown in Table 1. There were no statistically significant differences between baseline characteristics for subjects in study group 1 compared with study group 2. Fifteen subjects were enrolled, with nine subjects participating in each study section. For logistical reasons, some patients were unable to complete the second study, with three subjects participating in both study sections. As expected, CF patients with airflow obstruction and a low body mass index had impaired exercise capacity.


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  		Table 1. Characteristics of the study population

 
Study 1.   Table 2 shows the group mean ± SE data for control and added VD values collected at end exercise. Maximal O2 (O2 max), peak exercise workload, and HR were all significantly lower with added VD compared with the control study. End-tidal PCO2 (PETCO2) was significantly higher in the added VD study at end exercise. There was a significant increase in Borg dyspnea score in the added VD study. There was no significant difference in Borg leg discomfort between the two studies (not shown). Group mean and individual data for O2 max are shown in Fig. 1. Figure 2 shows group mean ± SE data for E and SaO2 during submaximal exercise and at end exercise. Ventilation at end exercise was not statistically different between the two studies. Ventilation at matched submaximal workloads was significantly higher in the added VD study compared with control. There was significant arterial desaturation during exercise in both the control and added VD studies. There was no significant difference between SaO2 at rest, submaximal exercise, or end exercise between the control and added VD studies.


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  		Table 2. Study 1: values obtained at end exercise

 


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  		Fig. 1. Study 1 group mean and individual data (n = 9) for maximal oxygen consumption at end exercise. VD, dead space.

 


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  		Fig. 2. Study 1 group mean ± SE values (n = 9) for minute ventilation (E; top) and arterial oxygen saturation (SaO2; bottom) at end exercise and at matched submaximal work rates.

 
Study 2.   Table 3 shows the group mean ± SE maximal exercise values for control and added VD/O2 studies collected at end exercise. O2 max and peak exercise workload in the added VD/O2 studies were significantly greater than in the control studies. Group mean and individual exercise O2 max are shown in Fig. 3. SaO2 was significantly higher at end exercise in the added VD/O2 study vs. the control study. Borg scale dyspnea and leg discomfort were the same at end exercise in both studies. Figure 4 shows group mean ± SE data for E and SaO2 during submaximal exercise and at end exercise. Peak E at end exercise was higher in the added VD/O2 study compared with control. E at matched submaximal workloads was significantly higher in the added VD/O2 study compared with control. As expected, SaO2 was significantly higher in the added VD/O2 study than in the control group throughout exercise.


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  		Table 3. Study 2: values obtained at end exercise

 


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  		Fig. 3. Study 2 group mean and individual data (n = 9) for maximal oxygen consumption at end exercise.

 


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  		Fig. 4. Study 2 group mean ± SE values (n = 9) for E and SaO2 at end exercise and at matched submaximal work rate.

 
Table 4 shows the breathing pattern during exercise in the control and added VD/O2 study. Added VD/O2 resulted in a slower, deeper breathing pattern. The increase in E during exercise is initially largely due to an increase in VT but later is primarily due to an increase in respiratory frequency as VT plateaus. This breathing pattern was also observed with added VD in study 1 (data not shown).


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  		Table 4. Study 2: comparison of breathing pattern during control and added VD/O2 studies at matched ventilation

 
Using linear regression, we examined possible predictors of increased exercise workload. Variables tested were drop in O2 saturation during control study, forced expiratory volume in 1 s (% predicted), O2 reached (% predicted), resting SaO2, E-to-MVV ratio predicted, and increase in E seen with added VD. There was no significant relationship between increase in exercise workload with O2 and these variables.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The major findings of this study of adults with CF are 1) stressing the respiratory system with added VD impairs exercise capacity with no change in peak exercise ventilation or SaO2 but with a significant fall in peak HR. This indicates that ventilatory limitation or arterial hypoxemia contribute to exercise limitation. And 2) added VD with supplemental O2 causes an improvement in exercise capacity with an increase in peak exercise ventilation. This indicates that arterial hypoxemia is a significant limiting factor during maximal exercise in these adult patients with CF.

Patients with moderate to severe CF have reduced exercise capacity (6, 9, 10, 16, 22, 28). It has been suggested that this is due to a combination of lung disease, poor nutrition, and peripheral muscle dysfunction. Recently, there has been increasing focus on the role of nutritional status and peripheral muscle dysfunction during exercise, suggesting that these factors, rather than respiratory function, limit maximal exercise capacity (4, 13, 14, 17, 23). Although these factors may influence exercise capacity, it is possible that pulmonary dysfunction, either abnormal mechanics or gas exchange, contributes to exercise limitation in CF. It is not known whether patients with moderate to severe CF are limited by respiratory factors. If maximal exercise in patients with CF is limited by ventilatory function, then at end exercise they should approach or reach their maximum ventilatory capacity. Use of resting measurements, and in particular the MVV, to predict maximum ventilatory capacity may be problematic and may not be reliable in predicting the presence of ventilatory limitation (2, 3, 15, 20). Apart form theoretical concerns about the MVV, the observation that in CF patients peak E exceeds MVV (6, 16, 28) indicates that MVV may underestimate the true maximum ventilatory capacity. These results support the findings that caution must be undertaken when ventilatory limitation during exercise is predicted using measurements such as MVV.

To determine whether exercise is limited by respiratory factors, we applied a selective stress to the respiratory system during exercise with added VD as used in previous studies of normal subjects (42, 44) and in patients with lung disease (5, 26). The addition of VD in normal subjects results in an increased E, which is maintained throughout exercise but has no effect on exercise duration. In patients with ILD, added VD results in a significant reduction in exercise duration, peak O2, and peak work rate with no difference in E at end exercise (26). This reduction in maximal exercise capacity with added VD is also seen in patients with CAL (5); however, unlike patients with ILD, patients with CAL are capable of reaching a significantly higher E with added VD. The reduction in maximal exercise capacity seen with added VD suggests that maximal exercise performance in ILD and CAL is limited by respiratory factors.

In CF patients, added VD during exercise results in a significant reduction in exercise tolerance, suggesting that maximal exercise performance is limited by respiratory factors. In contrast to normal subjects (42, 44), our patients did not have sufficient reserve to overcome the additional stress of added VD, and this resulted in a significant reduction in maximal exercise capacity. This suggests that CF patients are unable to continue exercise beyond a certain level of ventilation and that, in some cases, the maximum ventilatory capacity may have been reached. In addition, our patients also demonstrated a significant fall in SaO2 during both control and added VD studies, suggesting that arterial hypoxemia may also have limited maximal exercise performance.

To further evaluate whether arterial hypoxemia limits maximal exercise in CF patients, we examined the effects of supplemental O2 on maximal exercise capacity. If patients with CF are limited by arterial hypoxemia, then exercising with supplemental O2 should improve exercise capacity. Nixon et al. (34) found that supplemental O2 was of no benefit during exercise. Coates et al. (9) demonstrated that the increase in work seen with high levels of supplemental O2 was no different from that seen in normal subjects breathing high inspired O2 fraction. In a more recent study, Marcus et al. (29) found that, in severe CF patients with a mean desaturation of 12% during a control exercise test, supplemental O2 improved maximal exercise capacity. In their study, patients at end exercise had the same peak E in the control and supplemental O2 studies, suggesting that, at matched work rates, E in the supplemental O2 study was lower than that during the control study. This suppression of E associated with hyperoxia could explain the improved exercise capacity, since patients with ventilatory limitation should take longer to reach their maximum ventilatory capacity and so increase exercise duration. This is an important mechanism previously described in studies of supplemental O2 during exercise in patients with CAL and ILD (18, 25, 40).

To overcome the suppressive effects of hyperoxia on E, we added VD during the exercise test on supplemental O2. With supplemental O2, CF patients reached a higher E at end exercise and greater exercise workload than on room air. The ability to increase maximal E in the presence of sufficient supplemental O2 to prevent significant arterial desaturation leads to the conclusion that maximal exercise in this patient group is primarily limited by arterial hypoxemia rather than pulmonary mechanics.

It is important to note that preventing arterial hypoxemia only resulted in a small increase in maximal exercise capacity, indicating that additional factors also limit maximal exercise capacity in CF patients. At end exercise with supplemental O2 and added VD, subjects had an increase in PETCO2, suggesting that, once arterial hypoxemia has been prevented, maximal exercise capacity may be limited by ventilatory function. This will require further study and cannot be concluded from our data because increases in end-exercise PETCO2 have been observed in normal subjects exercising with added VD (44).

Limitations of experimental methods.   Measuring ventilation and expired gas concentrations under hyperoxic conditions may lead to measurement errors when O2 max is determined (38, 46). If this is so, we would expect progressive differences in O2 at increasing submaximal workloads between control and hyperoxic condition. We examined O2 during submaximal exercise in a patient that desaturated to <92% and found that O2 max at matched workloads was identical, suggesting that measurement error due to increased inspired O2 fraction was unlikely to have been the cause for the differences in O2 max observed with supplemental O2 (data not shown). There are also concerns about whether factors limiting maximal exercise were the same in the two study populations. Although this would not change the overall conclusions, Table 1 shows that baseline characteristics were very similar between the two study groups. Absolute O2 max was higher at end exercise in the control arm of study 2 compared with study 1, although this was not statistically significant. Also, when converted to percent predicted, the difference is only 4%, indicating that the differences in O2 max between the two patient groups are a result of differences in height, age, and gender. These factors would not be expected to result in different mechanisms of exercise limitation between the two groups.

Arterial hypoxemia and exercise limitation in CF.   It is unclear why arterial hypoxemia limits exercise in CF patients. Arterial O2 desaturation occurs frequently during maximal exercise in patients with CF (6, 10, 19) and is likely to be due to combinations of elevated venous admixture, ventilation/perfusion mismatch, intrapulmonary shunting, and alveolar hypoventilation. Patients with CF have been shown to have an increased venous admixture at rest that persists throughout exercise (12, 16). In a study of a small number of CF patients using the multiple inert gas elimination technique, Dantkzer et al. (12) demonstrated that venous admixture reduces slightly during exercise, largely as a result of improved ventilation/perfusion matching, and in the majority of cases this improvement in venous admixture is sufficient to maintain arterial PO2. This study also demonstrated that there was no evidence of diffusion impairment contributing to arterial desaturation. It has also been shown that, in some patients with CF (6, 10), arterial desaturation is associated with increases in PETCO2, suggesting that alveolar hypoventilation may play a role in arterial hypoxemia at end exercise. In a study looking at O2 saturation during exercise, Henke and Orenstein (19) found considerable variation in gas exchange during exercise in CF patients. The majority of their patients maintained their O2 saturations throughout exercise. Some patients desaturated with a fall in PETCO2, suggesting ventilation/perfusion mismatch with alveolar hyperventilation, whereas a significant number increased their PETCO2, suggesting alveolar hypoventilation. It is clear that the gas-exchange abnormalities observed during exercise in CF patients are complicated and require further study. This is important because, based on our findings, therapeutic interventions that improve gas exchange during exercise could improve maximal exercise capacity.

The mechanism of improved exercise capacity with supplemental O2 may include increased O2 availability to exercising muscles or reduced sensation of dyspnea associated with preventing arterial hypoxemia. Because significant arterial hypoxemia is most marked at end exercise, it is possible that supplemental O2 improved end-exercise O2 delivery to exercising muscles, which improved exercise performance.

Another possible mechanism is that supplemental O2 reduced the sensation of dyspnea at end exercise. In both studies, added VD caused an increase in VT at a given level of ventilation (Table 4). We found that, in study 1, added VD alone was associated with a mild increase in dyspnea sensation at end exercise that has also been observed in patients with idiopathic pulmonary fibrosis (26). This was not seen in study 2 when supplemental O2 was used with added VD, despite patients reaching a significantly higher E and PETCO2. It is possible that preventing hypoxemia improved exercise capacity by decreasing perception of dyspnea intensity normally caused by a combination of high E and arterial hypoxemia (37, 43), although whether arterial hypoxemia contributes to dyspnea independent of the effect on ventilatory muscle activity is not fully known (7, 24, 36, 41).

In conclusion, we found that adult patients with CF, with moderate to severe lung disease and desaturation during maximal exercise, are limited by respiratory function and that arterial hypoxemia is a significant limiting factor.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by the Health Research Board, the Cystic Fibrosis Research Trust, and the Cystic Fibrosis Association of Ireland. E. F. McKone was supported by the Irish Lung Association Fellowship Grant.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. G. Gallagher, Dept. of Respiratory Medicine, St. Vincent's Univ. Hospital, Elm Park, Dublin 4, Republic of Ireland (e-mail: cggall{at}eircom.net)

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
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