INTRODUCTION

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Aerobic exercise in cystic fibrosis (CF) is limited by the inability of the cardiorespiratory system to compensate for the increase in metabolic demands inherent to sustained effort. Regular exercise in patients with CF has been associated with improved aerobic exercise endurance and quality of life (1). Several training schedules have attempted to improve pulmonary function and exercise tolerance in patients with CF with varying success (2, 4). In a recent study, Nixon and colleagues demonstrated that patients with CF with greater aerobic exercise tolerance also had improved survival (7).

However, the type of exercise (aerobic versus anaerobic) employed during training may have different effects on improvement of exercise tolerance. Aerobic exercise training may not always improve baseline pulmonary function or weight gain in patients with CF (2). Anaerobic exercise training, such as weight lifting, achieved significant improvements in body weight and muscle strength (6). Such effects are not surprising because interval training, a technique that employs repeated bouts of anaerobic exercise, ultimately leads to significant improvements in aerobic exercise performance in both athletes and in individuals with obstructive lung disease (8). Thus, improvements in anaerobic exercise tolerance may lead to improvement of aerobic capacity in CF.

Daily activity frequently requires repeated bouts of anaerobic exercise (climbing a flight of stairs or short sprints to catch a bus) rather than performance of sustained, aerobic efforts. Therefore, understanding of anaerobic exercise performance may be of more practical importance in the daily life of a patient with CF than assessment of the more classic concept of aerobic exercise endurance. Despite extensive research on anaerobic exercise, it remains unclear whether patients with obstructive lung disease, such as in CF, have limited anaerobic capacity. The primary components that could account for such a decline also remain unclear, although Boas and colleagues recently reported a strong positive correlation in adolescent male patients with CF between the Wingate Anaerobic Test performance and body mass index (9).

We hypothesized that anaerobic exercise is compromised in patients with CF. However, since anaerobic exercise involves short and intense bursts of activity, we suspected that malnutrition, rather than the severity of lung disease, will affect anaerobic exercise capacity. To determine this, we compared graded exercise tests (aerobic) to anaerobic exercise in 17 CF and 17 matched control subjects and attempted to establish the influence of pulmonary function and nutritional status on aerobic and anaerobic exercise.

	METHODS

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Subjects

Seventeen subjects with CF and 17 age- and sex-matched control subjects were studied. Subjects with CF were recruited from the Division of Pediatric Pulmonology at Childrens Hospital Los Angeles. All subjects had pulmonary symptoms, signs, and radiologic changes consistent with CF and were diagnosed by pilocarpine iontophoretic sweat chloride tests. All subjects with CF were treated with pancreatic enzymes, vitamins, and bronchodilators. Some subjects with CF were also receiving antibiotics at the time of the study. Subjects with CF were studied when clinically stable, either as outpatients or at the end of a 2- to 3-wk hospital stay.

Control subjects were healthy adults recruited from members of the hospital staff and their families. No control subjects smoked or had cardiopulmonary disease.

Informed consent was obtained from each subject. The study was approved by the Institutional Review Board of Childrens Hospital Los Angeles.

Pulmonary Function Testing

All subjects underwent pulmonary function testing in the Pulmonary Function Laboratory at the Childrens Hospital Los Angeles, located at sea level (mean atmospheric pressure, 751 mm Hg). All measurements for each subject were performed on the same day. The vital capacity (VC) and its subdivisions were measured from a slow exhalation with a wedge spirometer (Model 3000; Medscience, St. Louis, MO). The best forced vital capacity, forced expiratory volume in 1 s (FEV₁), and mean forced expiratory flow during the middle half of forced vital capacity (FEF_25-75%) obtained from forced expiration into the wedge spirometer were selected and corrected for body temperature, pressure saturated (BTPS). Functional residual capacity was measured with a body pressure plethysmograph (2800 Autobox; Sensormedics, Yorba Linda, CA) by the method of Dubois and coworkers (10). Residual volume (RV) and total lung capacity (TLC) were calculated, and the RV/TLC ratios were determined from the actual values. Individual test results were analyzed and considered abnormal if they were greater than ± 2 SD from available reference values appropriate for age, height, and gender (11).

Nutritional Assessment

Nutritional assessment, consisting of anthropometric measurements and the calculation of lean body mass, was performed. Anthropometry included the triceps, biceps, anterior superior iliac, and subscapular skinfolds and were measured using Lange skinfold calipers. Six measurements were taken at each site, and the average of the six was used in calculations. Midarm circumference, height, and weight were also measured. Lean body mass (LBM) and arm muscle area (AMA) were derived from standard equations (15).

Exercise Testing

During all exercise tests subjects breathed through a mouthpiece from which inspired and expired gas concentrations were continuously analyzed with a rapid response zirconium O₂ and infrared CO₂ analyzers using a computerized breath-by-breath exercise system (Sensormedics 4400; Sensormedics). Inhaled and exhaled tidal volumes were measured with a turbine digital volume transducer (Sensormedics 4400; Sensormedics). From these, the following gas exchange parameters were measured on a breath-by-breath basis: minute ventilation (E), oxygen consumption (O₂), carbon dioxide production (CO₂), respiratory exchange ratio (RER = CO₂/O₂), and ventilatory equivalents for oxygen (E/O₂) and carbon dioxide (E/CO₂). Heart rate was continuously monitored by electrocardiogram and oxygen saturation (S_pO₂) determined by pulse oximeter (Nellcor Inc., Hayward, CA). Breathing reserve was calculated from the equation: breathing reserve = maximal voluntary ventilation (MVV)  peak E. MVV was estimated as FEV₁ × 35.

Graded Maximal Aerobic Exercise Testing

This initial test was designed to establish peak oxygen uptake (O₂max) of each subject, anaerobic threshold (AT), and peak E, and allow determination of the exercise load to be applied during anaerobic exercise. After assessment of baseline cardiorespiratory measures at rest, the test consisted of pedaling an electronically braked bicycle ergometer starting at zero load with increases in load of 8 watts (50 kilopondmeters [kpm]/min) every 30 s until the subject was unable to sustain a pedaling frequency of  40 rotations per minute (rpm) for the assigned load (19). The load at which the test was discontinued was recorded. The highest O₂ achieved during the last 30 s of exercise was recorded as the individual's O₂max. AT was determined from cardiorespiratory records as the point at which CO₂ increased out of proportion to O₂ (22). Subjects were allowed to rest for a minimum of 2 h prior to beginning any anaerobic exercise testing.

Anaerobic Exercise Testing

Subjects underwent two bouts of supramaximal exercise tests at a workload approximately 130% of the workload recorded at O₂max during the graded exercise test. In each bout, baseline cardiorespiratory parameters were monitored while subjects sat immobile on the ergocycle, breathing room air. When values became stable over a period of 60 s, zero load pedaling was allowed for 1 min, after which subjects pedaled at the designated load (130% of O₂max). Subjects were encouraged to maintain a pedaling frequency of around 70 rpm. The test was discontinued when the subject could no longer maintain a pedaling frequency of  40 rpm.

Within 2 wk of completion of this exercise protocol, subjects underwent a second identical anaerobic exercise test. The average of the two anaerobic bouts was used to determine the duration of anaerobic exercise, anaerobic performance (anaerobic performance = workload in kpm/min × average time of exercise in minutes), maximal E, and peak heart rate.

Data Analysis

Data are presented as mean ± SD. Two-tailed paired t tests were used to evaluate potential differences within each of the two groups (aerobic versus anaerobic in CF or controls). Unpaired t tests were used to compare differences between the two groups. Unpaired t tests were used to compare clinical characteristics, pulmonary function values, and anthropometric data between the two groups. When multiple comparisons were made, a Bonferroni adjustment to alpha was incorporated into the analysis.

The relationships of aerobic and anaerobic variables (O₂max, AT, anaerobic performance), pulmonary function values (FEV₁, VC, FEF_25-75%, RV/TLC), and anthropometric data (AMA, LBM) were assessed by linear regression analysis and calculation of Pearson correlation coefficients. In all tests, p < 0.05 was considered significant.

	RESULTS

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Seventeen patients with CF and 17 normal subjects were studied. Most subjects with CF showed moderate obstructive disease by pulmonary function testing, and all had some degree of hyperinflation. Control subjects had normal pulmonary function tests. In subjects with CF, AMA and LBM were all markedly reduced. Resting S_pO₂ was slightly lower in subjects with CF. Clinical characteristics, pulmonary function values, and anthropometric data are shown in Table 1.

Aerobic Exercise

Subjects with CF showed significantly lower peak E, O₂max, heart rate (HR), exercise duration, and peak workloads compared with control subjects. Significant oxygen desaturations, defined as a change > 5%, did not occur during aerobic exercise, and mean S_pO₂ at exhaustion were similar. Mean end-tidal oxygen pressure (PET_O2) and end-tidal carbon dioxide pressure (PET_CO2) at peak exercise were also similar. When AT was expressed as a function of individual O₂max (%O₂max), no significant differences occurred in the two study groups (Table 2).

Anaerobic Exercise

Subjects with CF had significantly lower minute ventilation at the end of anaerobic exercise than did control subjects. In subjects with CF peak E at the end of anaerobic exercise was similar to peak E at the end of aerobic exercise (p = NS). In contrast, control subjects had significantly lower peak E at the end of anaerobic exercise when compared with their peak E at the end of aerobic exercise. During anaerobic exercise, neither the CF group nor the control group developed significant oxygen desaturation, although S_pO₂ was lower in CF at the end of anaerobic exercise. Anaerobic performance was significantly lower in CF subjects compared with control subjects (p < 0.005), although bout duration was similar in both study groups (p = NS). Comparison of peak anaerobic values are shown in Table 3.

Correlation of Pulmonary Function and Nutritional Status to Exercise

Potential correlations between pulmonary function and nutritional status to aerobic and anaerobic exercise were explored (Table 4).

Aerobic performance (O₂max and AT) in control subjects did not exhibit significant correlations with any pulmonary function measures. In subjects with CF, however, AT displayed a significant positive relationship to FEV₁, suggesting that pulmonary function contributes to some degree to aerobic performance.

Anaerobic performance was significantly correlated to AT and O₂max in control subjects. In subjects with CF, anaerobic performance correlated with O₂max, but not with AT, suggesting that aerobic and anaerobic exercise tolerance do not correlate as well in CF (Figure 1). In subjects with CF prediction of anaerobic exercise tolerance from aerobic parameters (O₂ and AT) was not as good as in controls.

View larger version (21K): [in this window] [in a new window]   Figure 1.   Correlation of O2max to anaerobic performance in subjects with CF (closed squares) and control subjects (open circles). In subjects with CF linear regression correlation coefficient (r) = 0.65 (p < 0.01). In control subjects linear regression correlation coefficient (r) = 0.78 (p < 0.001).

Aerobic performance was not correlated to LBM or AMA in either subjects with CF or control subjects. Anaerobic performance, however, correlated significantly to both LBM and AMA in both CF and control subjects (Figure 2).

View larger version (23K): [in this window] [in a new window]   Figure 2.   Correlation of lean body mass to anaerobic performance in CF subjects (closed squares) and control subjects (open circles). In subjects with CF linear regression correlation coefficient (r) = 0.69 (p < 0.01). In control subjects linear regression correlation coefficient (r) = 0.85 (p < 0.001).

	DISCUSSION

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In this study, we demonstrated that aerobic and anaerobic exercise performance are decreased in CF when compared with control subjects. In control subjects, however, there was significant correlation between aerobic capacity (O₂max and AT) and anaerobic performance. In subjects with CF anaerobic exercise performance did not correlate as well to aerobic exercise performance. This may be because aerobic exercise in CF is limited by both cardiovascular and pulmonary mechanisms. Our analysis has shown muscle mass to be the factor with the highest correlation coefficient with anaerobic exercise performance in our subjects with CF, whereas pulmonary function did not correlate. This suggests that pulmonary function has little or no effect on the ability to perform high intensity, short duration exercise.

Aerobic Exercise

It is well established that in chronic lung disease, aerobic exercise capacity is decreased and is limited not only by pulmonary mechanisms, but also by poor nutritional status (23). The pulmonary limitation to aerobic exercise may involve an increase in PET_CO2, an increase in E/O₂ ratio, or arterial oxygen desaturation. Coates and coworkers (26) have previously demonstrated CO₂ retention associated with severe pulmonary mechanical impairment and increased dead space to tidal volume ratios in subjects with CF. Also, peak E during aerobic exercise in an individual with chronic lung disease is usually very close to maximal voluntary ventilation, suggesting that these patients have little or no ventilatory reserve.

Individuals with advanced lung disease have a decreased FEV₁, which is thought to contribute to their exercise limitation. However, the decrease in O₂max in chronic lung disease may only be partially explained by the decrease in FEV₁ (23). In adults with chronic obstructive pulmonary disease (COPD), Baurle and Younes (23) found that decreased inspiratory capacity correlated to aerobic exercise performance. They noted that in subjects with COPD of similar severity, there was a variability in ventilatory equivalent for oxygen (E/O₂) that correlated with aerobic exercise limitation (23). Also, Coates and colleagues have previously suggested that poor nutritional status and muscle wasting may lead to limitation of exercise tolerance in children with CF (27).

In this study, we found that O₂max, AT, duration of exercise, peak HR, and maximum workload were all decreased in subjects with CF compared with control subjects. Neither the CF group nor the control group had significant oxygen desaturation during aerobic exercise. Resting arterial oxygen saturation was also not markedly different between the control group and the CF group, reflecting the mild to moderate lung involvement of our subjects. Subjects with more severe pulmonary involvement would probably have displayed lower arterial oxygen saturation at rest and during exercise (29). Indeed, Henke and Orenstein found that subjects with CF with lower FEV₁ (FEV₁ < 50%VC) were more likely to have a significant (> 5%) decrease in oxygen saturation during exercise (30).

Anaerobic Exercise

Anaerobic performance is decreased in subjects with CF when compared with normal subjects. Peak heart rate at the end of anaerobic exercise was also significantly lower in the CF group than in the control group. As in aerobic exercise, no significant oxygen desaturation was found during anaerobic exercise in either the CF group or the control group.

Little is known about anaerobic exercise in individuals with chronic lung disease. It is difficult to analyze anaerobic exercise ability, since parameters of gas exchange (O₂, AT, E/ O₂, E/CO₂) are difficult to measure and interpret during anaerobic exercise bouts. One must rely on such parameters as heart rate, time of exercise, minute ventilation, and workload in an attempt to quantitate anaerobic exercise. As mentioned above, only subjects with CF with mild or moderate lung disease entered the study. Including a more severe group might have revealed further information during correlation analysis of anaerobic performance. However, in such subjects the extent of disease might have had a negative impact on performance variability and reproducibility.

Relationship of Pulmonary Function to Exercise

No significant relationships were identified between pulmonary function and anaerobic exercise in CF or control subjects. Cabrera and colleagues have suggested that reduced anaerobic performance in CF is associated with diminished pulmonary function (31). Our data, however, are similar to that of Boas and coworkers who found no correlation between pulmonary function and anaerobic performance (9).

In healthy individuals cardiovascular, rather than pulmonary, mechanisms are the limiting factor in aerobic exercise, explaining the lack of correlation of aerobic exercise to pulmonary function. Significant pulmonary reserve at peak aerobic exercise is present, such that minute ventilation during maximal aerobic exercise rarely exceeds 60-80% of maximal voluntary ventilation. In addition, peak minute ventilation at the end of anaerobic exercise was lower than at peak aerobic exercise in control subjects, suggesting that pulmonary mechanics do not contribute to anaerobic performance in healthy individuals. In contrast, subjects with CF had similar peak minute ventilation at the end of anaerobic exercise when compared with peak minute ventilation at the end of aerobic exercise. A significant contribution of pulmonary function to aerobic exercise does exist in CF, explaining the aerobic exercise limitation. However, there does not appear to be any association of pulmonary function with anaerobic exercise in CF subjects. Anaerobic exercise in CF appears to be limited by factors other than those which limit aerobic exercise.

Relationship of Muscle Mass to Exercise

Although the total amount of anaerobic work was decreased in the CF group, the total length of time that the CF group could perform anaerobic exercise was the same as for the control group. The ability of muscle to perform anaerobically may be viewed as a function of two factors, the efficiency of muscle contractions and the length of time a particular amount of work can be sustained.

In both the CF and control groups, anaerobic performance correlated highly to lean body mass and arm muscle area. In analogy to the fact that poor aerobic performance in CF is multifactorial, and not only secondary to decreased pulmonary function, the decrease in anaerobic performance in CF may not just be secondary to poor nutrition, but also to altered muscle metabolism. This issue has been controversial in CF. Lands and colleagues have previously reported that subjects with CF performed similarly to control subjects during sprint work when corrected for lean body mass (32). These investigations suggested that the nutrition-related decrease in exercise performance in CF may reflect a loss of muscle mass, not a loss of performance of the existing muscle (32). When comparing anaerobic exercise to lean body mass, Boas and coworkers suggested that CF muscle does not perform as well as in healthy subjects (9). Further delineation of this loss of performance may lead to better understanding of muscle metabolism during anaerobic exercise.

Boas and colleagues (9) used the Wingate Anaerobic Test to study anaerobic exercise. This test involved 30-s bouts of all-out exercise. In our study, the load for anaerobic exercise was determined from the graded exercise test in order to better standardize across individuals with different levels of daily activity of physical training. Using this method, we have shown that subjects with CF could sustain an anaerobic bout of exercise for a similar length of time.

These data raise several issues regarding the performance and energy production of skeletal muscle in CF during anaerobic exercise. Medbo and Tabata have demonstrated that approximately 2 min of exercise to exhaustion are required to fully use anaerobic energy sources (33). It has also been suggested, however, that aerobic energy production via oxidative phosphorylation may provide some energy during short exercise bouts in healthy muscle (34). Thus, the relative energy contribution from aerobic and anaerobic energy sources would vary depending on the subject (CF versus control) and type of anaerobic exercise employed. Since anaerobic exercise is of short duration, it would be reasonable to assume that the majority of energy for anaerobic exercise comes from sources already stored in resting muscle. The duration of anaerobic exercise probably depends minimally on the ability of the cardiorespiratory system to deliver oxygen to working muscle. Therefore, at comparable intensities, subjects with CF in our study were able to sustain pedaling for similar lengths of time as control subjects.

	CONCLUSION

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Decreased aerobic exercise capacity in chronic lung disease has previously been documented. However, the study of anaerobic exercise has been relatively scarce in respiratory disease and particularly in CF. Our study demonstrates significant reductions in anaerobic exercise capacity in subjects with CF, which seem to be primarily determined by muscular factors rather than pulmonary function. We speculate that improving nutritional status (muscle mass) will improve anaerobic exercise performance in CF.

Daily activity frequently involves bursts of anaerobic exercise and reduced pulmonary function may not be as detrimental to daily activities as previously thought. Subjects with CF could sustain anaerobic exercise for similar durations as normal subjects. We postulate that the efficacy of an exercise training program in CF, directed toward improving daily activity requirements, could be substantially improved by emphasizing anaerobic, rather than aerobic, routines.