Physiological Responses to Arm and Leg Exercise in Women Patients with Chronic Fatigue Syndrome Casimiro Javierre, MD, PhD José Alegre, MD, PhD José Luis Ventura, MD, PhD Ana García-Quintana, MD, PhD Ramon Segura, MD, PhD Andrea Suarez, MD Alberto Morales, MD Agusti Comella, MD, PhD Kenny De Meirleir, MD, PhD
ABSTRACT.
Patients affected by chronic fatigue syndrome (CFS) characteristically show easy and unexplained fatigue after minimal exertion that does not resolve with rest and is associated with specific sympCasimiro Javierre, Ramon Segura, Andrea Suarez, Alberto Morales, and Agusti Comella are affiliated with the Department of Physiological Sciences II, Medical School. IDIBELL (Campus of Bellvitge), University of Barcelona, Spain. José Alegre is affiliated with the Department of Internal Medicine, Hospital of Vall d'Hebrón, Barcelona, Spain. José Luis Ventura is affiliated with the Department of Physiological Sciences II, Medical School. IDIBELL (Campus of Bellvitge), University of Barcelona, Spain. He is also affiliated with the Department of Intensive Care, University Hospital of Bellvitge, L'Hospitalet (Barcelona), Spain. Ana García-Quintana is affiliated with Delfos Medic Center, Chronic Fatigue Syndrome Unit, Barcelona, Spain. Kenny De Meirleir is affiliated with the Department of Human Physiology, Faculty of Physical Education and Physical Therapy, Vrije University, Belgium. Address correspondence to: Casimiro Javierre, Department of Physiological Sciences II, Medical School. IDIBELL (Campus of Bellvitge), University of Barcelona, Ctra. Feixa Llarga s/n 08.907, L'Hospitalet de Llobregat, Barcelona, Spain (E-mail:
[email protected]). Journal of Chronic Fatigue Syndrome, Vol. 14(1) 2007 Available online at http://jcfs.haworthpress.com © 2007 by The Haworth Press, Inc. All rights reserved. doi: 10.1300/J092v14nOl_05 43
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toms lasting for more than six months. Cardiopulmonary exercise testing is a valid procedure for determining functional capacity in patients with CFS. We compare cardioventilatory adaptation to exercise between a group of eightyfive consecutive women patients affected by CFS and a group of fifteen healthy women extremely sedentary individuals, with the use of maximum incremental exercise testing on a cycle ergometer and arm ergometer, assessing possible differences. The majority of values achieved at peak exhaustive exercise were significantly lower in CFS patients than controls, including the percentage of maximum oxygen uptake in arm physical test (37.4 ± 10.0% in CFS vs. 58.9 ± 15.8% in controls) and leg physical test (53.4 ± 15.0% in CFS patients vs. 76.2 ± 18.0% in controls). In conclusion, the CFS group shows a lower work capacity in arm or leg exercise that would not be justified exclusively by their personal characteristics or deconditioning. doi: 10.1300/J092v14n01_05 {Article copies available for a fee from The Haworth Document Delivery Service: 1-800HAWORTH. EWebsite: mail address: © 2007 by The Haworth Press, Inc. All rights reserved.}
KEYWORDS. Chronic fatigue syndrome, maximal oxygen uptake, lactate
INTRODUCTION Patients affected by Chronic Fatigue Syndrome (CFS) characteristically show easy and unexplained fatigue after minimal exertion (I) that does not resolve with rest and is associated with specific symptoms lasting for more than six months. Various peripheral physiological mechanisms (2), immune deregulations (3,4) or central disorders (5) have been proposed to explain this syndrome. Several authors have reported decreased aerobic capacity relative to normal subjects in these patients, with reductions in maximum oxygen uptake (V02max), peak heart rate and peak power output (6,7,8,9), whereas others describe aerobic capacity at the lower end of the normal range (10). These differences could be due to the fact that the CFS population is very heterogeneous, or to the small populations studied. Cardiopulmonary exercise testing is a valid procedure for determining functional capacity, the maximum oxygen uptake being a standard parameter to estimate a person's functional reserve. Exercise on a cycle ergometer or treadmill, where performance involves the lower extremities, is typically used to assess aerobic capacity. Exercise testing results
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can be used to differentiate between groups of patients who present symptoms consistent with CFS, classifying impairment as none, mild, moderate, or severe (11), although the association between exercise capacity and activity limitation is moderate (12). This study compares cardioventilatory adaptation to exercise between a group of patients affected by CFS and a group of extremely sedentary individuals, with the use of maximum incremental exercise testing on a cycle ergometer and arm ergometer. MATERIALS AND METHODS The CFS group comprised 85 consecutive women patients with a mean weight of 64.4 ± 11.9 kg and height of 1.61 ± 0.06 m referred to the Department of Physiological Sciences II of the University of Barcelona for a battery of examinations. All met the CDC criteria for CFS (13) and diagnoses were confirmed in all patients by consensus of two physicians. No alternative diagnoses were established in any patient over a minimum of six months of additional observations. Fifteen healthy women with a mean weight of 57.5 ± 5,1 kg and height of 1.59 ± 0.05 m served as the control group and sex-, age-, height- and weight-matched CFS group. The controls were considered to be extremely sedentary subjects on the following basis: their occupation did not require physical effort, they did not perform physical activity and all their other activities (hobbies, etc.) were sedentary activities. All participants were fully informed of the procedures, discomfort, and the risks involved in performing the examinations. The study was approved by the Ethics Committee of the Research Institute of Bellvitge Hospital (IDIBELL-Bellvitge Campus, Barcelona). Written consent was obtained from all subjects after informing them of the procedures to be used and the risks entailed. Laboratory Exercise Tests Exercise testing was done in the Department of Physiological Sciences II laboratory at a room temperature of22-24°C and relative humidity of 5565%. The subjects were instructed not to perform 'intensive physical activity during the 72 hours prior to the evaluations. Tests were always conducted in the morning after a light breakfast. Each subject was firsttested on an arm ergometer (model Angio, Lode, Groningen, The Netherlands) at a frequency of 40-50 rev·min-1. The
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initial load was l0 w; with consecutive increases of l0 w every one minute until the subject could no longer maintain the target power output despite strong vocal encouragement. After a recovery period of 10 min, the participants were tested on a precalibrated Monark cycle ergometer (model 818E, Varberg, Sweden), starting with 0 watt at 50 rev·min-1 for 2 min, with consecutive increases of 12.5 watt everyone minute until exhaustion. O2 uptake and CO2 production were measured by an automatic gas analysis system (model Metasys TR-plus, Brainware S.A., La Valette, France) equipped with a pneumotacograph and making use of a two-way mask (Hans Rudolph, Kansas, USA). Age-based predicted values for VO2max were calculated from regression equations derived from maximal testing in a cohort of healthy sedentary women (VO2max in mL·kg-1 . min-l = 42.3 - [0.356· age in years]) (14). Heart rate (HR) was monitored continuously using a pulsometer (model Polar Accurex Plus, Polar Electro OY, Finland). The age-predicted maximum heart rate was calculated with the following formula: [208 - (0.7· age in years)] (15). Arm blood pressure (BP) was taken manually using a clinical sphygmomanometer. Blood lactate concentration was measured after the arm ergometer test and the cycle ergometer test (YSI 1500 SPORT, YSI Incorporated, Ohio, USA). The rating of perceived exertion (RPE) (16) was recorded after all workloads. Statistical Analysis Analysis of variance for repeated measures was performed to assess group differences for the various samples. An independent student t-test was performed to assess group differences for resting parameters. The level of significance was set at P < 0.05 for all the statistical tests. All data are expressed as the mean ± SD. RESULTS Resting Parameters There were no significant differences in the resting physiological parameters between the CFS patients and the controls, except for the following: systolic BP, 120A± 5.3 mmHg in CFS vs.105.6 ± 15.1 mmHg
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in controls (P < 0.01); diastolic BP, 79.9 ± 12.0 mmHg in CFS vs. 69.2± 8.2 mmHg in controls (P < 0.05); and RPE 10.3 ± 2.3 in CFS vs. 6.0 ± 0.0 in controls (P < 0.001).
Arm and Cycle Ergometer Test Differences Values at peak exercise in the arm ergometer test are shown in Table 1. The majority of values achieved at peak exhaustive exercise were significantly lower in CFS patients than controls, including the percentage of maximum oxygen uptake (37.4 ± 10.0% in CFS vs. 58.9 ± 15.8% in controls). For the peak workload, linear regression analysis determined the line of best fit, defined as: VO2theoretical peak = 0.370 + (workload· 0.01043) Where VO2theo!etical peak (theoretical oxygen uptake pea~) is in 1· min-1 and workload IS given In watts (95% CI=0.272-0.469 l'mIn-1, r=0.548, P < 0.001). Peak exercise values in the leg ergometer test are also shown in Table 1. Again, most of the values achieved at peak exhaustive exercise were significantly lower in the CFS patients as compared with the control group, including the percentage of maximum oxygen uptake (53.4± 15.0% in CFS patients vs. 76.2 ± 18.0% in controls).
Comparison Between Arm and Leg Performance There were no significant differences between the groups in arm/leg ratio for V02max' workload, or HR (Table 2).
DISCUSSION The first aim of the present study was to assess the potential differences in physiological adaptation to exercise between women patients with CFS and the normal population. To prevent a gender-related influence, our patient population was 90% women, a percentage consistent with the control group (88%), and higher than the ratio reported in other study of approximately three women diagnosed for every man (17). As potential factors that could influence the results, some authors have suggested that maximum oxygen consumption may not be achieved by the exercise protocol used or that the endpoint fo~' maximum effort may not
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TABLE 2. Comparison between arm and leg exercise for different physiological variables between the CFS and the control groups. Variable Arm/Leg VO2max (%) Arm/Leg Work load (%) Arm/Leg HRmax (%)
CFS group
71.9 55.5 93.4
± ± ±
Control group
Significance
20.3
75.2 ± 13.0
>0.05
18.1
45.7 ± 9.1
>0.05
9.3
88.2 ± 7.5
>0.05
be well-established (J 8, 19,7,9). To avoid this influence, a protocol was designed for the arm and cycle ergometer testing using small increases in workload that could be completed by physically inactive persons. The criteria identifying maximum effort were the same for both the patient and control groups. In CFS group, ] 1 % of the patients reached maximal effort using the American College of Sports Medicine Guide to Exercise Testing. This subgroup of CFS patients show similar differences respect the control group with a decrease of 35.2% in maximal oxygen uptake and of 37.8% in the maximal workload. A factor to explain the fatigability and low exercise tolerance of CFS patients is the "hypoactivity syndrome" and its deconditioning-related effects on physiological responses and exercise capacity (8). These characteristics make it particularly difficult to obtain a control group with similar activity levels. Selection for our control group required more than one year of extremely sedentary lifestyle, that is, very sedentary work, not walking to work, no hobby/leisure activities requiring any physical effort, no physical activity, and no obligations that would increase physical activity, such as owning a pet that needed walking. These requirements are different from the term "sedentary" as it is used to define normal, healthy individuals who are not engaged in regular, structured physical activity, which describes most individuals (20). Strict selection of the control group meant that the resting parameters were comparable for weight, height, or ventilatory function. In contrast, the rating of perceived exertion was high with respect to the controls who, in all cases indicated an absence of fatigue. These findings are consistent with the concept that CFS symptoms include fatigability at rest, according to various diagnostic criteria (1). Blood pressure was higher in the CFS group, which could be related to the fact that patients with CFS show alterations in measures of sympathetic and parasympathetic nervous system function (21), with a more stressful response at rest during the test.
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The arm ergometer testing showed an important difference in the work capacity done in the specific physical test. The CFS group reached only 53.4% of the power output obtained by the controls, while the two groups showed similar ratings of perceived exertion. All parameters related to the load achieved demonstrated significant differences, with oxygen consumption 78.4% higher in the control group, and lactate production 76.3% higher. The cycle ergometer test showed an even more important difference in the work capacity done in the specific physical test. The CFS group reached only 45.9% of the power output obtained by the control group, at a similar rating of perceived exertion. All parameters related to the load achieved showed significant differences, with 63.5% higher oxygen consumption in the control group and 94.3% higher lactate production. When the arm ergometry data were related to the cycle ergometry data, the results were analogous for both groups, with 73.6% oxygen consumption observed in the arms as compared to the legs. These findings are similar to those reported by other authors (22) and would imply the same decrease in work capacity regardless of the various muscle groups used. In the group with an extremely sedentary life style for more than one year (virtually the entire group had a similar lifestyle throughout their entire adult life), there was a 24% decrease in 02 uptake with respect to predicted values. This could result from a "hypoactivity syndrome" and its deconditioning-related effects on physiological responses and exercise capacity. In contrast, the CFS patients showed a decrease of 47% in 02 uptake with respect to predicted values which, although partly explained by the above reasons, should be considered along with the CFS diagnosis to justify a 23% higher decrease with respect to predicted values than in the control group. It should be considered that there is a CFS-dependent decrease in performance. The maximum parameters obtained by our CFS group were lower than those found by other authors (23,24). The ratio between the predicted values of peak oxygen uptake by specific formulas for CFS patients showed a moderate correlation with the data measured in our group. Indirect calculation of peak oxygen uptake using the formula proposed by Mullis et al. (23) showed a difference of -2.2% (95% CI = -7.9,3.4). Respect to the formula proposed by Nijs and De Meirleir (24) a deviation of 12.1 % occurred (95% CI=6.8-17.4), within the mean error of the prediction for the formula submitted by these authors. Nevertheless, the comparison between the different groups is difficult because in some of them, the percentage of men/women is different (23) and, in the other, the maximum load reached is significantly greater (49.7 ± 24.8 vs.
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85.5 ± 28.9) (24). Something similar could occur with the formula proposed in our paper for indirect calculation of peak oxygen uptake in arm exercise, which, although a good tool for our population. group, would need specific modifications depending on the group studied or an increase in the number of patients studied, based on a multicenter design. In summary, it appears that the decrease in the peak workload achieved in arm or leg exercise by CFS patients would not be justified exclusively by their personal characteristics or deconditioning. REFERENCES I. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Intern Med 1994; 121: 953-959. 2. Evengard B, Schacterle RS, Komaroff AL. Chronic fatigue syndrome: New insights and old ignorance. J Intern Med 1999; 246: 455-469. 3. Nijs J, Demanet C, Mcgregor NR, De Becker P, Verhas M, Englebienne P, De Meirleir K. Monitoring a hypothetical channelopathy in chronic fatigue syndrome: Preliminary observations. JCFS 2003; II: 117-133. 4. Nijs J, De Meirleir KD, Meeus M, McGregor NR, Englebienne P. Chronic fatigue syndrome: Intracellular immune deregulations as a possible aetiology for abnormal exercise response. Med Hypotheses 2004; 62: 759-765. 5. Geargioades E, Behan WM, Kilduff LP, Hadjicharalambous M, Mackie EE, Wilson J, Ward SA. Chronic fatigue syndrome: New evidence for a central fatigue disorder. Clin Sci (London) 2003; 105: 213-218. 6. De Becker P, Roeykens J, Reynders M, McGregor N, De Meirleir K. Exercise capacity in chronic fatigue syndrome. Arch Intern Med 2000; 160: 3270-3277. 7. Fulcher KY and PD White. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neural Neurosurg Psychiatry 2000; 69: 302-307. 8. Inbar 0, Dlin R, Rotstein A, Whipp BJ. Physiological responses to incremental exercise in patients with chronic fatigue syndrome. Med Sci Sports Exerc 2001; 33(9): 1463-1470. 9. Riley MS, O'Brien CJ, McCluskey DR, Bell NP, Nicholls DP. Aerobic work capacity inpatients with chronic fatigue syndrome. Br Med J 1990; 301: 953-956. 10. Sargent C, Scroop GC, Nemeth PM, Bumtet RB, Buckely JD. Maximal oxygen uptake and lactate metabolism are normal in chronic fatigue syndrome. Med Sci Sports Exerc 2002; 34: 51-56. II. Vanness JM, Snell CR, Strayer DR, Dempsey IV L. Stevens SR. Subclassifying chronic fatigue syndrome through exercise testing. Med Sci Sports E>::erc 2003; 35 (6): 908-913. 12. Nijs J, De Meirleir K, Wolfs S, Duquet W. Disability evaluation in chronic fatigue syndrome: Associations between exercise capacity and activity limitations/participation restrictions. Clin Rehabil2003; 18: 139-148.
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RECEIVED: 03/31/05 ACCEPTED: 09/26/05 doi: 10.1300/J092vI4n01_05
