Energy cost of activity and exercise in children and adolescents with cystic fibrosis

Journal of Cystic Fibrosis 5 (2006) 53 – 58 www.elsevier.com/locate/jcf

Energy cost of activity and exercise in children and adolescents with cystic fibrosis Mark R. Johnson *, Thomas W. Ferkol, Ross W. Shepherd Department of Pediatrics, Washington University School of Medicine. St. Louis, MO, United States Received 29 March 2005; received in revised form 8 October 2005; accepted 12 October 2005 Available online 15 December 2005

Abstract In cystic fibrosis (CF), perturbations of total daily energy expenditure (TDEE) may be a major determinant of altered nutrition and growth. Measurement of TDEE is problematic, though the flex-heart rate method (FHRM) provides a close estimation of TDEE, as compared to the cost-prohibitive, gold standard, the double-labeled water method, and permits estimates of the energy cost of daily activities (ECA) above resting energy expenditure (REE). We hypothesize that alterations in ECA affects TDEE in CF. Purpose: To measure components of TDEE in adolescents with CF and normal lung function compared with controls, and to determine whether ECA can be improved by diet and exercise. Methods: Clinically stable CF subjects (aged 9 – 13, n = 12) and age- and gender-matched controls (n = 13) had repeated measurements of TDEE by FHRM, REE, and maximal cardiopulmonary exercise testing (CPET) during a 6-week exercise and diet program. Results: While the mean REE was similar in both groups, ECA was significantly lower in CF adolescents as compared to controls ( p = 0.02). During CPET, maximal exercise in CF was characterized by hyperventilation, which was unrelated to ventilation – perfusion mismatching. There were no changes in REE after dietary intervention. Conclusion: ECA in CF adolescents with normal lung function is lower when compared to healthy controls. These findings support the hypothesis that clinically stable patients with CF have inefficient energy metabolism or alternatively conserve energy during activities of daily living. D 2005 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Energy expenditure; Cardiopulmonary exercise testing

1. Introduction Cystic fibrosis (CF) is the most common lethal genetic disease in Caucasians. Its adverse impact on nutritional status is well recognized. Several studies have identified a strong relationship between malnutrition and mortality [1,2]. Nutritional deficiencies are related to alterations in energy metabolism in persons who have CF, which are multifactorial. Low energy intake, decreased energy absorption and increased energy expenditure are all documented in CF * Corresponding author. Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, 660 South Euclid Avenue, St. Louis, Missouri, 63011, United States. Tel.: +1 314 454 4030; fax: +1 314 454 2412. E-mail address: shepherd _ [email protected] (M.R. Johnson).

patients [3]. In particular, resting energy expenditure (REE) appears to be increased per unit cell mass in malnourished children with CF [4 – 8], which cannot be completely explained by pulmonary inflammation [4]. Nevertheless, the later development of abnormal pulmonary mechanics may cause further increases with age [5– 8]. Knowledge of REE alone provides only an incomplete assessment of total daily energy expenditure (TDEE), and does not provide any information regarding the energy cost of daily activities (ECA), which may be an important contributor to altered energy balance in diseases such as CF. The development of the doubly-labeled water (DLW) technique has permitted determination of TDEE in free living humans, and early studies in CF have showed either normal [9] or increased [10] TDEE in this disease. At present, however, the cost of the DLW method is prohibitive and DLW is

1569-1993/$ - see front matter D 2005 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jcf.2005.10.001

54

M.R. Johnson et al. / Journal of Cystic Fibrosis 5 (2006) 53 – 58

unavailable for this purpose. TDEE can be also be estimated by flex-heart rate method (FHRM), activity diaries or accelerometry. Of available alternatives to DLW, the FHRM provides the closest estimation of TDEE, and has the advantage of providing information on ECA. Indeed, the FHRM has been validated against the DLW by Livingstone et al. [11]. The FHRM relies on the physiological relationship between heart rate (HR) and activity, and the fact that this increase is closely relate to EE above resting levels. The technique involves measuring REE, and deriving individual correlation of HR to EE over five energy levels of activity. TDEE can then be calculated from the resultant regression equations [11,12], and 24-h heart rate monitoring. The ECA for a 24-h day can then be calculated from the TDEE and REE. In this study, we report findings with respect to TDEE, REE, ECA and maximal cardiopulmonary exercise testing of clinically stable CF adolescents with normal lung function. We hypothesized that in healthy CF patients, compared to controls, that the ECA is altered due to inefficiencies of energy metabolism during activities such as exercise. In addition, we studied the potential for improving energy efficiency of activity by an exercise and diet program, such as that observed in athletes undergoing intensive training.

2. Methods 2.1. Subjects Clinically stable persons with CF (n = 12), aged 8 – 21 were recruited from the Washington University Cystic Fibrosis Center at Saint Louis Children’s Hospital. Healthy age-, gender-, and developmentally-matched controls (n = 13) were recruited from the community. Enrollment criteria included: ability to perform CPET, forced expiratory volume at 1 s (FEV1) consistently greater than 50% for the 2 years before to enrollment, no history of diabetes, liver dysfunction or hepatosplenomegaly, and no contraindication to participation based on pre-participation screening. Patients were not studied during an active pulmonary exacerbation. Informed written consent was obtained form each participant and their parents, and the studies were approved by the Washington University School of Medicine Human Studies Committee. 2.2. Design All patients and controls had initial REE and TDEE determined using the FHRM and maximal CPET testing. Persons with CF were evaluated on 3 occasions, while controls were evaluated only once during the study period. At the time of enrollment, clinical data was obtained and no interventions were performed during a 6-week wash-in period to assess repeatability of measurements. During the second phase, the participants were randomized to either: (a)

a graded exercise program combined with carbohydrate supplements or (b) a graded exercise program combined with fat supplements. Supplements equaled 50% of their REE. Patients on the carbohydrate arm of the study received RESOURCE\ Fruit Beverage supplement. Participants on the fat arm received Scandishakes\ with cream so that the supplement had at least 50% lipid content. The exercise program was supervised three times weekly for 6 weeks. Exercise was individualized to the participant and was entirely aerobic. Sessions were monitored by a member of the research team. A heart rate equal to 60% of the HRmax was sought during these sessions which lasted 45– 60 min. At initiation and completion of the 6-week exercise program, the studies were repeated and EE re-measured. 2.3. REE and FHRM Fasting REE was determined in the early morning with a metabolic cart (Sensormedics 2900) by measuring expiratory oxygen uptake (V O2), carbon dioxide excretion (V CO2) over a 20– 40 min period. The manual radial pulse was measured every 5 min. After measurement of REE, participants had a standardized snack (one Nutrigrain bar* per 20 kg weight and 8 oz whole milk). They were then asked to perform routine spirometry including forced vital capacity (FVC), and FEV1. Participants were then fitted with electrocardiograph monitoring equipment, a headset and mouthpiece for measurements of heart rate (by EKG), V CO2, V O2, respiratory quotient (RQ), and EE / m (as calculated by Weir equation) within the Sensormedics 2900 metabolic cart. Participants then proceeded to perform a 5-Step activity program where they exercised 5 min at 5 separate levels of activity (sitting, standing, and progressive walking (1, 2, and 2 MPH with 3% grade). Values were time averaged by 30 s. 2.4. Maximal CPET After obtaining the 5-step activities, the participants were then encouraged to progress through an exercise protocol on a Sensormedics 800S cycle ergometer starting at 0 W resistance for 3 min then progressing by 10 W/min until V O2max was obtained. V O2, V CO2, (Ve), end-tidal O2 (ETO2), and end-tidal CO2 (ETCO2)work, and HR (by EKG) were measured. 2.5. TDEE and ECA After testing, the ‘‘flex point’’ (defined as the average of the highest resting heart rate and lowest activity heart rate) was determined. Linear regression of HR versus EE / m above the ‘‘flex point’’ was calculated using the least squares method by SPSS software. HR data was then measured for 24– 72 h using a Polar 610 heart rate monitor (Polar Electro, Kempele, Finland). This consists of an electronic chest strap transmitter and wrist watch where heart rate data is stored in a memory to be later downloaded to a personal computer for analysis. TDEE was then calculated based on the downloaded

M.R. Johnson et al. / Journal of Cystic Fibrosis 5 (2006) 53 – 58

2500 Energy expenditure (calories/d)

HR data using the FHRM. EE below the flex point was calculated as being equal to REE. EE above the flex point was calculated from the regression equation relating HR to EE / m. The ECA was calculated as the difference between TDEE and REE. 2.6. Statistical analyses

3. Results For enrollment, we had broad inclusionary criteria and sought to recruit persons with CF from 8 to 21 with mild and moderate lung disease. Despite this we were only able to recruit CF patients who were all 9 – 13. All had normal lung function and mild pulmonary disease. The characteristics of study are given in Table 1. Of the 12 subjects with CF enrolled into the study, 10 subjects completed the entire study and 2 subjects (both males) withdrew from the study after the first exercise testing session. One subject with CF had nonphysiologic results (i.e., TDEE = 5730 calories/day) and was excluded from analysis. 21 controls were enrolled and of these 8 had completed puberty and were excluded from analysis to match the recruited CF participants. These 13 age, gender-, and Tanner stage-matched controls were compared to our CF population. 176 of 180 exercise sessions were supervised by a member of the research team. Of the 4 missed sessions compliance of the sessions was verified with a heart rate monitor. Compliance with the use of the supplements was verified during the supervised exercise sessions. Heart rate data was collected for 24 – 72 h every 15 s. We experienced difficulties with a newly remanufactured chest strap that was stiffer than previous models and conformed poorly to smaller chests (i.e., children). We recollected data if recordings were inadequate. Data points were downloaded Table 1

M:F Age (years) Bone age (years) Tanner (pubic hair) Wt (kg) Ht (m) BMI (kg/m2) FEV1 (% predicted)

6:5 12.7 12.1 2.9 44.3 1.50 19.6 103

Control 8:5 11.2 10.2 2.5 43.3 1.46 19.9 106

P value 0.74 0.10 0.11 0.53 0.84 0.52 0.84 0.69

1500

1000

ECA

500

REE CF

NCF

Fig. 1. Measured energy expenditure in cystic fibrosis adolescents. The mean REE (white columns) was similar between healthy CF and non-CF adolescents (1393 calories/day and 1290 calories/day, respectively; p = 0.17). In contrast, the mean ECA (gray columns) in CF adolescents was significantly lower compared to non-CF subjects (267 calories/day and 769 calories/day, respectively; p = 0.02).

into an excel spreadsheet and averaged for time of day (i.e., data for 01:10.15 was averaged with 01:10:15 data for the next day and 16:58:45 was averaged with 16:58:45). The averaged data was used for analysis of TEE by the heart rate method. Values for REE and ECA are shown in Fig. 1. Mean REE was 1393 calories/day in CF and 1290 calories/day in our control population, which was not statistically significant ( p = 0.17). However, the mean ECA was different in healthy CF adolescents compared to control subjects (267 calories/ day and 769 calories/day, respectively; p = 0.02). There were no statistically or clinically significant changes in EE after intervention with diet and exercise (see Fig. 2). 2000

1600

1200

800

400

0 CF

2000

0

Energy expenditure (calories/d)

Differences between patients and controls at end exercise were analyzed by comparing the means for measured values, and p-values less than 0.05 were considered statistically significant. Differences in study results (except for end exercise data) between: CF patient and control groups were analyzed using standard student T-tests. Calculation of the best fit straight line correlating EE / m to HR (for HR values greater than the ‘‘flex point’’), was performed using the ‘‘least squares’’ method.

55

ECA REE E

Pre

Post

Carbohydrate

E

Pre

Post

Lipid

Fig. 2. Measured energy expenditure in cystic fibrosis adolescents following dietary and exercise interventions. CF patients began a monitored, six-week exercise program after they were randomized to either carbohydrate or lipid supplementation groups. Both REE (white columns) and ECA (gray columns) were measured before and after interventions. There were no significant changes in EE after intervention with exercise and either dietary regimen.

56

M.R. Johnson et al. / Journal of Cystic Fibrosis 5 (2006) 53 – 58

The exercise characteristics of the CF subjects are shown in Fig. 3. Maximum V O2 was higher in controls but when corrected for height (based on established norms for height, [13]) was similar (Fig. 3a). Ve (Fig. 3b), RQ (Fig. 3c) and VeO2 (Fig. 3d) were consistently higher in individuals with CF. These findings suggest that those with CF hyperventilate during exercise (compared with controls) to obtain a similar V O2. ETO2 (Fig. 3e) was higher and ETCO2 (Fig. 3f) lower in our population of patients with CF (with normal lung function) suggesting that any hyperventilation seen in this population of CF patients was not a result of V/Q mismatching. In summary, maximal exercise in this population of patient with CF was characterized by a degree of hyperventilation (increased Ve, RQ and VeO2) that did not appear to be the result of ventilation – perfusion mismatching. Despite this, maximal oxygen uptake is similar between individuals with CF and controls.

a.

4. Discussion In this study, we found that CF adolescents with normal pulmonary function controls had lower ECA than healthy controls. REE was not elevated overall in the CF patients, contrary to some, but not all, earlier studies, though alterations in body composition (lower cell mass in CF, expanded extracellular water, without changes in total body weight) may explain this finding [4]. The ECA of a 24-h day is a function of the intrinsic metabolism of the individual and the amount of activity the individual partakes. We did not measure activity so it is unclear if our subjects with CF had less activity (which we suspect) or had an intrinsic metabolic difference from controls. It is possible that there is bioconservation of overall energy expenditure with a reduction in spontaneous activity. Alternatively, CF patients may simply be relatively inactive due to other limitation from their disease. If alterations in metabolism are

b.

1.5

75 70 65

1.3

Ve

VO2

1.4

60

1.2 55 1.1

50 -60

-50

-40

-30

-20

-10

-60

0

-50

-40

Time

-30

-20

-10

0

Time

c.

d. 50

1.20

45

VeO2

1.15

RQ

1.10 1.05

40 35 30

1.00

25 -60

-50

-40

-30

-20

-10

-60

0

-50

-40

Time

e.

-20

-10

0

f.

122

38 36

ET CO2

120

ET O2

-30

Time

118 116

34 32 30

114

-60

-50

-40

-30

Time

-20

-10

0

-60

-50

-40

-30

-20

-10

0

Time

Fig. 3. Exercise characteristics of persons with cystic fibrosis. The exercise characteristics of CF adolescents were measured as described in Methods. (a) The expiratory oxygen uptake (V O2) was similar between CF adolescents ( ) and non-CF subjects ( ); while (b) carbon dioxide excretion (V CO2); (c) respiratory quotient (RQ); and (d) ventilatory equivalent for oxygen (VeO2) were consistently higher in CF adolescents, which suggested that CF individuals hyperventilate during exercise as compared to controls to obtain a similar V O2. (e) End tidal oxygen (ETO2) is higher, and (f) end tidal carbon dioxide (ETCO2,) is lower in those with CF indicating that hyperventilation observed in this healthy CF population with normal lung function was not a result of V/Q mismatching.

M.R. Johnson et al. / Journal of Cystic Fibrosis 5 (2006) 53 – 58

suspected, we suggest future studies either study energy metabolism of standardized activities such as those described by Richard et al. [14], or quantitate activity with a measure such as accelerometry. We were unsuccessful in changing EE by dietary manipulation and exercise during this 6-week trial. We based our intervention on the concept of ‘‘fat adaptation’’ wherein normal individuals are able to increase lipid usage by a combination of cardiovascular exercise and a high fat diet [15 – 17]. Unlike these studies in healthy persons, where the intrinsic RQ of the individuals decreased, our CF patients randomized to lipid supplements had no change in the resting RQ measured during determination of REE. Our inability to achieve ‘‘fat adaptation’’ may have been a result of inadequate lipid absorption or inadequate lipid intake per day. Alternatively, during our supervised exercise sessions, we may have been unsuccessful in achieving the level of exercise as is needed to achieve fat adaptation. Similar to previous studies [18,19], we noted that individuals with CF studied at maximal exercise had a higher degree of ventilation compared with similar controls. The degree of ventilation did not seem to be a result of ventilation – perfusion mismatching which was suggested by other studies. Our population had normal lung function as measured by FEV1 (average 102%, range 82 – 125% predicted) so it is unlikely that they had significantly increased dead space ventilation. Likewise, ETO2 increased and ETCO2 decreased at end exercise, which argues against ventilation – perfusion mismatch playing a dominant role in hyperventilation. Other causes of the elevated Ve could include voluntary hyperventilation or metabolic differences intrinsic to CF. In both CF and control subjects, increased activity is chiefly fueled by greater utilization of carbohydrates. In addition, normal individuals are able to increase their use of lipids as an energy source during exercise [15 –17,20] and exercise programs are able to increase the intrinsic betaoxidation of lipids [20]. If, as we suspect, there is impaired in lipid utilization in CF patients, any increase in activity would have to be fueled by increased carbohydrate utilization. This utilization of carbohydrates would in turn increase V CO2, Ve and the RQ. Indeed, we demonstrated all these characteristics during our study. This may be a basis for the inefficiency in mitochondrial oxidation [21,22] which has also been described in persons with CF. Likewise, there appears to be impaired muscle function in CF. Specifically, there are work limitations in persons with CF even when adjusted for muscle mass [23] or when similar control populations are recruited [22]. If as we suspect, beta-oxidation of lipids is impaired in CF, this inefficiency may contribute to a decreased ability perform work in those with CF. Finally, we had hypothesized that impairments in energy metabolism could be corrected by exercise and increased fat supplementation, but we were unable to demonstrate changes in EE with such interventions. This failure may

57

be because a) our underlying hypothesis that alterations in EE could be improved by fat supplementation and exercise was incorrect, b) our intervention was insufficient to demonstrate a positive effect, or c) the problem is intrinsic to those with CF and cannot be corrected by simple intervention (i.e., diet and exercise). If there is an intrinsic defect in lipid metabolism in those with CF, it likely plays a role in the malnutrition that occurs in CF. Similarly, alterations in energy metabolism may cause individual with CF to fatigue quicker than peers, further decreasing activity. Clearly, additional studies into role of lipid metabolism in CF are needed to better understand these findings.

Acknowledgements The authors wish to thank Debb White R.P.F.T., R.R.T, Pamela Bates C.R.T.T., C.P.F.T., R.P.S.G., Gratia Telthorst and Sherrie Martin for their expert technical support during this project. We would also like to thank Lori Harper and Bradley Weinberger who were invaluable in their support of this project. We would also like to thank Washington University Cystic Fibrosis Center staff for their assistance in recruiting subjects. The work reported in this manuscript was supported by the Cystic Fibrosis Foundation. Finally, all research conformed to NIH guidelines, and the protocol was reviewed and approved by the Washington University School of Medicine Human Studies Committee.

References [1] Bell SC, Bowerman AR, Davie CA, Campbell IA, Shale DJ, Elborn JS. Nutrition in adults with cystic fibrosis. Clin Nutr 1998;17:211 – 5. [2] Corey M, McLaughlin FJ, Williams M, Levison H. A comparison of survival, growth and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol 1988;41:583 – 91. [3] Elborn JS, Bell SC. Nutrition and survival in cystic fibrosis. Thorax 1996;51:971 – 2. [4] Thomson MA, Wilmott RW, Wainwright C, Masters B, Francis PJ, Shepherd RW. Resting energy expenditure, pulmonary inflammation and genotype in the early course of cystic fibrosis. J Pediatr 1996;129: 367 – 73. [5] Bell SC, Saunders MJ, Elborn JS, Shale DJ. Resting energy expenditure and oxygen cost of breathing in patients with cystic fibrosis. Thorax 1996;51:126 – 31. [6] Shepherd RW, Greer RM, McNaughton SA, Wotton M, Cleghorn GJ. Energy expenditure and the body cell mass in cystic fibrosis. Nutrition 2001;17:22 – 5. [7] Bell SC, Nixon LS, Ireland RP, Elborn JS, Shale DJ. Resting energy expenditure during infective exacerbation in cystic fibrosis. Am J Respir Crit Care Med 1994;A673. [8] Stallings VA, Rung EB, Hofley PM, Scanlin TF. Acute pulmonary exacerbation is not associated with increased energy expenditure in children with cystic fibrosis. J Pediatr 1998;132(3):493 – 9. [9] Shepherd RW, Holt TL, Vasques-Velasques L, Coward WA, Prentice A, Lucas A. Increased energy expenditure in young children with cystic fibrosis. Lancet 1988;1:1300 – 3. [10] Bronstein ML, Davies PS, Hambidge KM, Accurso FJ. Normal energy expenditure in the infant with presymptomatic cystic fibrosis. J Pediatr 1995;126:128 – 33.

58

M.R. Johnson et al. / Journal of Cystic Fibrosis 5 (2006) 53 – 58

[11] Livingstone MB, Prentice AM, Coward WA, et al. Simultaneous measurement of free-living energy expenditure by the doubly labeled water method and heart rate monitoring. Am J Clin Nutr 1990;52: 59 – 65. [12] Livingstone MB, Prentice AM, Coward WA, Ceesay SM, Strain JJ, McKenna PG, et al. Daily energy expenditure in free-living children: comparison of heart-rate monitoring with the doubly labeled water method. J Clin Nutr 1992;56:343 – 52. [13] Cooper DM, Weiler-Ravell D. Gas exchange response to exercise in children. Am Rev Respir Dis 1984;129(Suppl):S47 – 8. [14] Richard ML, Davies PSW, Bell SC. Energy cost of physical activity in cystic fibrosis. Eur J Clin Nutrit 2001;55:690 – 7. [15] Helge JW, Wulff B, Kiens B. Impact of a fat-rich diet on endurance in man: role of the dietary period. Med Sci Sport Exerc 1998;30: 456 – 61. [16] Lambert EV, Speechly DP, Dennis SC, Noakes TD. Enhanced endurance in trained cyclists during moderate intensity exercise following 2 weeks adaptation to a high fat diet. Eur J Appl Physiol 1994;69:287 – 93. [17] Phinney SD, Bistrian BR, Evans WJ, Gervino E, Blackburn GL. The human metabolic response to chronic ketosis without caloric restric-

[18] [19]

[20] [21]

[22]

[23]

tion: preservation of sub-maximal exercise capability with reduced carbohydrate oxidation. Metabolism 1983;32:769 – 76. Cerny FJ, Pullano TP, Cropp GJ. Cardiorespiratory adaptations to exercise in cystic fibrosis. Am Rev Respir Dis 1982;126:217 – 20. Hirsch JA, Zhang SP, Rudnick MP, Cerny FJ, Cropp GJ. Resting oxygen consumption and ventilation in cystic fibrosis. Pediat Pulmonol 1989;6:19 – 26. Horowitz JF, Klein S. Lipid metabolism during endurance exercise. Am J Clin Nutr 2000;72:558S – 63S [suppl]. de Meer K, Jeneson JA, Gulmans VA, van der Laag J, Berger R. Efficiency of oxidative work performance of skeletal muscle in patients with cystic fibrosis. Thorax 1995;50:980 – 3. Selvadurai HC, Allen J, Sachinwalla T, Macauley J, Blimkie CJ, Van Asperen PP. Muscle function and resting energy expenditure in female athletes with cystic fibrosis. Am J Respir Crit Care Med 2003;168:1476 – 80. Moser C, Tirakitsoontorn P, Nussbaum E, Newcomb R, Cooper DM. Muscle size and cardiorespiratory response to exercise in cystic fibrosis. Am J Respir Crit Care Med 2000;162:1823 – 7.