¹Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China

²Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China

³Institute of Human Nutrition, University of Southampton, UK

⁴Department of Medicine, Shatin Hospital, Hong Kong, People's Republic of China

Correspondence to: N L S Tang, Department of Chemical Pathology Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China E-mail: nelsontang@cuhk.edu.hk

^aCurrent address: The Lakeside Practice, Doncaster, DN6 0JB, UK.

Guarantor: N Tang and M Elia.

Contributors: NLST, JW and ME participated in the protocol design, data interpretation and main writing of the paper. MGJ designed the original study, developed the protocol and contributed to data interpretation. MLC carried out the experiments and participated in data interpretation and writing of paper. EH, CML, JKHL participated in protocol design, clinical data collection, discussion of core ideas and contributed to writing of the paper.

Objectives: To investigate total daily energy expenditure in chronic obstructive pulmonary disease (COPD) patients during a rehabilitation programme.

Design: Observational study involving a case and a control group.

Subjects: Ten COPD patients (six with body mass index (BMI) <18.5 kg/m² and four with BMI >18.5 kg/m²) were evaluated for their energy expenditure profile. Four additional healthy age-matched volunteers were also included for methodology evaluation.

Interventions: Measurements of total daily energy expenditure (TEE), resting energy expenditure (REE) and diet-induced thermogenesis (DIT) and energy intake were undertaken by indirect calorimetry and bicarbonate-urea methods and dietary records.

Results: REE in COPD patients was not significantly different from that predicted by the Harris-Benedict equation. Before the exercise day the mean TEE was 1508 kcal/day and physical activity level (PAL as calculated by TEE/REE) was 1.52. On the exercise day the TEE increased to 1568 kcal/day and PAL was 1.60, but neither of these changes were significant. The energy cost of increased physical activity during rehabilitation exercise was estimated to be 191 kcal/day. No significant change was found in DIT between the two patient groups. However, overall energy balances were found to be negative (-363 kcal/day).

Conclusion: The rehabilitation programme did not cause a significant energy demand in COPD patients. TEE in COPD patients was not greater than in free-living healthy subjects. Patients, who were underweight, did not have a higher TEE than patients with normal weight. This suggested that malnutrition in COPD patients was not due to an increased energy expenditure. On the other hand, a significant negative energy balance due to insufficient energy intake was found in seven out of 10 patients.

Sponsorship: The project was inpart supported by the Bristol Myers Squibb Unrestricted Nutrition Grant.

European Journal of Clinical Nutrition (2002) 56, 282-287. DOI: 10.1038/sj/ejcn/1601299

chronic obstructive pulmonary disease; rehabilitation program; total daily energy expenditure; physical activity level

Introduction

Patients with chronic obstructive pulmonary disease (COPD) frequently lose weight. Early reports suggested that 40-50% of such patients were underweight, and that weight loss is associated with poor clinical outcome, impaired body function and increased mortality (Schols et al, 1993; Gray-Donald et al, 1996; Landbo et al, 1999). Despite this, the mechanisms responsible for wasting remain poorly defined. They may be related to increased energy demand, due to a possible increase in total energy expenditure (TEE) or a reduction in energy intake. A combination of the two would exaggerate the energy deficit. Therefore, there is a theoretical possibility that increased physical activity, which is advocated in rehabilitation programmes of patients with COPD, could have adverse effects, especially if there is inadequate compensation in energy intake. It is clear that the effects of such programmes on energy turnover require evaluation.

TEE is typically divided into basal metabolic rate (BMR), which is normally the largest component of TEE (>60% of TEE), thermogenesis (mainly dietary induced thermogenesis (DIT), which accounts for about 10% of energy expenditure) and physical activity energy expenditure (PAEE). Patients with COPD have been reported to have a raised BMR (~10%), partly because of an increase in the energy cost of breathing (Creutzberg et al, 1998). However, there is no universal agreement on this issue, since Ryan et al found no increase in BMR in malnourished patients with COPD (Ryan et al, 1993). Wilson et al found an increased BMR in malnourished patients while BMR in those adequately nourished was not raised (Wilson et al, 1990). Similarly, there is controversy about changes in DIT in patients with COPD. Green & Muers (1991) reported increased DIT, whereas a number of other workers reported no increase in DIT (Hugli et al, 1993; Dore et al, 1997). PAEE is the most variable component of TEE, but unfortunately the least studied with reliable techniques. In general, patients with disease have reduced PAEE, partly because of the limitations imposed by the disease itself (eg arthritis, lethargy associated with inflammatory disease, shortness of breath, angina, or drug therapy; Elia & Jebb, 1992; Elia et al, 2000), and partly because of malnutrition (Elia, 1997). It is possible for the reduction in physical activity to compensate or more than compensate for any increase in BMR, so that TEE is either unaltered or decreased (Elia, 1995).

Surprisingly, a previous study that undertook measurements of free-living TEE using tracer techniques (doubly labelled water) suggested a possible increase in TEE. In the group of 10 patients with normal BMR studied by Baarends et al (body mass index (BMI) 24.4 kg/m²), the ratio of total energy expenditure (TEE)/BMR was found to be 1.78 (Baarends et al, 1997a,b). This value is higher than the mean values obtained by similar tracer studies in healthy elderly subjects (>65 y) who were incorporated into an international database (Elia et al, 2000). Furthermore, a number of national organizations suggest that the energy needs of subjects over 65 y are only about 1.5´BMR (eg DHSS in UK; Department of Health, 1991) which is well below the value of 1.78 reported by Baarends et al (1997a,b).

The aim of this study was to examine the changes in energy expenditure in COPD patients during a rehabilitation programme, with an emphasis on undernourished COPD patients. Since no such information exists in malnourished COPD patients, the study would provide insights into the energy requirements of these already wasted patients.

Methods

Subjects

Ten female patients with clinically stable COPD aged 74±9 y were recruited on the rehabilitation ward in Shatin Hospital of Hong Kong and divided into two groups according to whether their BMI was above or below 18.5 kg/m². The protocol was approved by the University Ethical Committee of Clinical Research at the Chinese University of Hong Kong and informed consent was obtained from all subjects. The characteristics of patients are shown in Table 1. Another four healthy subjects (aged 69-84 and mean BMI 19.5 kg/m²) without COPD were invited to participate in the study. They did not participate in the COPD rehabilitation programme but they had measurements of REE, TEE and dietary intake. The basic treatment regimen was standardised to inhaled ipratropium 40 µg and salbutamol 200 µg four times a day with minor modification according to symptoms.

Anthropometry and measurements of resting energy expenditure

The weight and height of the subjects were measured and used to calculate the BMI. Skinfold thicknesses were measured and used to calculate total body fat (and percentage body fat), as well as fat-free mass (Woo et al, 1988). Measurements of mid upper arm circumference and triceps skinfold thickness at the same level were used to calculate mid upper arm muscle circumference (AMC; Woo et al, 1988).

Resting energy expenditure (REE) was measured for 30 min after an overnight fast (10-14 h) using open circuit indirect calorimetry (Datex Instrumentation Corporation, Helsinki, Finland), with subjects in the recumbent position at an ambient temperature of 23±1°C. Post-prandial REE was also measured for a period of 30 min, 2 h after lunch, which consisted of a standard meal. This meal contained a total of 550 kcal derived from carbohydrate (50%), protein (25%) and fat (25%). The subjects ate the meal at different rates, but it was mostly eaten within 30 min. DIT was derived from the ratio of post-prandial to REE.

Measurement of total energy expenditure

TEE was measured with the bicarbonate-urea method on two consecutive days. The method is essentially an isotopic dilution technique for measuring CO₂ production. Details of the methodology are provided elsewhere, and very similar to that used in studies of patients with HIV, lung neoplasia, obesity, cystic fibrosis and healthy subjects (Elia et al, 1995; Paton et al, 1996; Gibney et al, 1997). In brief the subjects were given a constant infusion of labelled ¹⁴C-bicarbonate, following a priming dose of labelled urea and bicarbonate. When a near-equilibrium state was established, 24 h urine collections were started beginning at 09:00 h, and continued for 2 days. They were used to estimate the specific activity of urine urea using techniques described elsewhere (Elia et al, 1995). Background urine samples were collected before the infusion was begun. COPD patients took part in the rehabilitation exercise on the second measurement day. No exercise was prescribed on the first day. The exercise included a standardised rehabilitation activity, such as strength and stretching training. They included sub-maximal upper and lower limb ergometry at 50-80% VO_max and endurance training with controlled weights for 10 min three times a day. The duration and type of exercise undertaken were noted for calculation of energy cost of physical activity.

Dietary records and energy intake

All food and beverages were provided by the hospital kitchen. These and all the items not eaten at meals or snacks were also recorded by investigator and used to calculate total energy intake using food composition tables, which were on a computer program (Nutritionist 4-Diet Analysis and Nutrition Evaluation 1993, N-Squared Incorporated).

Calculations and statistical analyses

Energy expenditure was calculated from gaseous exchange (indirect calorimetry) using the equation of Elia and Livesey (1992): energy expenditure (kcal)=3.78 O₂+1.24 CO₂, where O₂ and CO₂ are in litres.

Total 24 h energy expenditure was calculated assuming the energy equivalent of CO₂ was 504 kJ (120.5 kcal) per mol CO₂ in a typical Chinese diet of 64% carbohydrate, 20.5% fat and 15.5% protein (Elia, 1991; Elia & Livesey 1992). The energy cost of physical activity was calculated by MET ratios, which took into account the duration of the activity, body weight of the subject and tabulated values of the energy cost associated with specific activities (Ainsworth et al, 1993). The physical activity level (PAL) was calculated as the ratio of TEE to REE. PAEE plus thermogenesis was calculated as the difference between TEE and REE. Energy balance was calculated as the difference between energy intake and TEE. Nitrogen (N) balance was calculated as the difference between N intake (assuming 1 g N=6.25 g protein) and N output, which was derived from urine urea nitrogen excretion plus 2 g of non-urinary loss.

Results are expressed as mean and standard derivation (s.d.). Statistical analyses were carried out using Pearson's correlation and Mann-Whitney test (SPSS Inc. Chicago, IL, USA). Intra-individual change was compared by paired-Wilcoxon test. A P-value less than 0.05 was considered to be statistically significant. Power analysis suggested that to achieve an 8.5% increase in TEE (effect size index of 0.85) in the same individuals with a 80% power and P<0.05 would require a sample size of nine (Cohen, 1988).

Results

The mean REE of the healthy elderly subjects was 934 kcal/ day, which corresponds to 93% of the Harris-Benedict prediction values. The mean TEE over two days was 1402 kcal/ day and the PAL, 1.56.

The characteristics of the COPD patients are shown in Table 1 together with their lung function and blood gas results, which were similar between the two subgroups. As expected the underweight group with a BMI less than 18.5 kg/m² had significantly lower skinfold thicknesses and total body fat (P<0.05) than the group with a BMI greater than 18.5 kg/m². However, their FFM and upper AMC were relatively well preserved and did not differ between the groups.

REE (kcal/day) was significantly lower in the underweight group (Table 2), but when expressed as a percentage of the Harris-Benedict prediction, there was no significant difference between the groups. Dietary-induced thermogenesis (DIT) 2 h after meal ingestion was similar between the two groups and was approximately 10 and 14% higher than REE in patients with a BMI <18.5 kg/m² and greater than 18.5 kg/m², respectively.

On the day before the rehabilitation programme TEE of all the 10 patients was 1508 kcal/day, and PAL at 1.52 on the day without participating in rehabilitation exercises (Table 3). There was no significant effect from the exercising day on TEE, PAL or PAEE and thermogenesis in either group of patients. The overall increase in the measured TEE on the exercise day was only 60 kcal/day (~6% of REE). Neither this or the increase in PAL were significant. From the activity records it was estimated that the energy expended in rehabilitation exercises was 191 kcal (19% of the REE or ~10% of TEE).

TEE in undernourished patients averaged at 1396 kcal/day before the rehabilitation day and 1527 kcal/day on the rehabilitation day (Table 3). PAEE plus thermogenesis was 456 and 587 kcal/day on these 2 days. The activity related energy expenditure did not differ significantly from those found in adequately nourished patients. The mean PAL among the undernourished patients increased from 1.48 to 1.63 on the day with rehabilitation exercise.

TEE (kcal/day) was related to predicted BMR (kcal/day) by the following equation, which was established by regression analysis: TEE=1.5´BMR (Harris-Benedict)+29 (r=0.63, P<0.05).

Nitrogen balance was close to zero in both groups of patients. However, both groups showed an overall negative mean energy balance of -363 kcal/day. Seven out of the 10 COPD patients apparently had a more than 200 kcal/day energy deficit.

Discussion

This study suggests that TEE in a group of undernourished patients undergoing rehabilitation is no greater than that of free-living individuals. Fuller et al (1996) reported a PAL value of 1.5 in a random sample of free-living elderly men of over 75 y. Another analysis of doubly labelled water studies in 100 elderly free-living women suggested that the mean PAL value was 1.60±0.25 (Elia et al, 2000). Therefore, a mean PAL value of 1.52 observed in COPD patients in this study was in keeping with the range PAL observed in the elderly by previous reports. A similar value was also observed in the other four healthy volunteers in this study. Baarends et al (1997,b) reported that the median PAL value in patients with COPD and normal REE was 1.78, which was significantly higher than a PAL value of 1.56 in another group of COPD patients with an elevated BMR. The reason for the discrepancy between their results and those of our study is not clear, but it may be related to differences in the severity of disease, and the nutritional status (only one of their patients had a BMI below 18.5 compared to six out of 10 patients in our study subjects) and gender (female in our study, male in their study). However, another recent study by whole body calorimetry on 16 male adequately nourished COPD patients with a mean BMI of 21 kg/m² suggested that TEE and PAL in patients with COPD were not higher than the control subjects (Hugli et al, 1996). They also showed a lower voluntary day-time activity in COPD patients by Doppler radar; however, the effect of rehabilitation programme in COPD patients was not studied (Hugli et al, 1996). These last observations are in keeping with the results of this study. They are also in keeping with the general conclusions about TEE obtained by doubly labelled water and bicarbonate urea method in patients with a range of diseases, which reveal no increase in TEE or PAL, and frequently a decrease in both (Elia et al, 2000).

It is perhaps surprising that severely debilitated patients had a PAL ratio as high as 1.5. The severe respiratory disease might be expected to limit physical activity because of breathlessness. However, it is possible that the energy cost of specific activities is increased in such patients or that the type and pattern of physical activity is altered so that patients undertake milder activities over longer periods of time. Our data from the activity diary is in keeping with the latter suggestion. The 10 patients were estimated to have spent a mean of 191 kcal/day during their rehabilitation programme according to the activity diary, whilst TEE increased non-significantly by only 60 kcal/day. It is possible that the respiratory incapacity prevented patients from increasing their energy expenditure further, and that they reduced their discretionary activities when not undertaking exercise. Another possibility relates to the day-to-day variability in TEE, which is estimated to be ~10% in healthy individuals. A similar variability in patients with COPD would lead to a variability in PAL of ~0.15, which could mask any changes produced by exercise on the rehabilitation day. The analysis is also confounded by the precision of the bicarbonate-urea method, but this is considered to have a relatively small influence (CV~2-3%, Leijssen & Elia 1996). The lack of a significant increase in TEE on the rehabilitation day does not mean that training is of no value. It may provide functional benefits, especially to the upper segment of the body, which was the focus of the training schedule (Tiep, 1997; Folgering & Rooyackers 1998), as well as psychological benefits which may aid recovery.

Different methods of measurement of TEE have their individual limitations. For example, although whole body calorimetry method using a respiratory chamber provides measurements of energy expenditure under carefully controlled conditions, it does not necessarily reflect TEE in a free-living condition. The doubly labelled water method provides estimates of TEE over a period of about 2 weeks, but it does not indicate the day-to-day variation in TEE. The labelled bicarbonate-urea method also estimates TEE in free-living conditions but provides estimates on a day-to-day basis. The method has been used on animals for decades and recently modified for use in human subjects (Elia et al, 1995). In common with the DLW method, it determines the TEE based on the daily production rate of CO₂. The rate of CO₂ generation is calculated from the extent of dilution of ¹⁴C-bicarbonate being infused subcutaneously at a constant rate. Subjects are allowed to carry out their usual daily activity and are fully ambulatory. The method allows the determination of energy expenditure on a daily basis. This study also demonstrates the practicalities of using the bicarbonate-urea method in this population of subjects. The infusion from the minipump was tolerated well by the subjects and there were no complications.

Energy balance was found to be negative but the N balance was close to zero. Under-reporting of dietary intake or under-assessment of portion sizes by photographs, would tend to favour negative balances of both N and energy. Further studies on these balances over longer periods of time coupled with changes in body weight and composition would be worthwhile undertaking.

In summary in this group of patients with severe COPD, it would seem that an energy intake close to 1.5´BMR is necessary to maintain a near energy balance. BMR predicted by Harris-Benedict's equation could be used to estimate the daily calorie requirement. However, some of the individuals were malnourished and could benefit from additional energy intake provided as meals, snacks or liquid supplements. Such benefits (eg walking distance, muscle strength) have been reported in a systematic review on the use of supplements in COPD patients. The benefits were likely to occur only in patients with a BMI less than 20 and only after an increase of at least 5% body weight (Stratton & Elia, 1999).

Ainsworth BE, Haskell WL, Leon AS, Jacobs DR Jr., Montoye HJ, Sallis JF, Paffenbarger RS Jr. (1993). Compendium of physical activities: classification of energy costs of human physical activities. Med. Sci. Sports Exerc, 25: 71-80. MEDLINE

Baarends EM, Schols AM, Pannemans DL, Westerterp KR, Wouters EF. (1997a). Total free living energy expenditure in patients with severe chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med, 155: 549-554.

Baarends EM, Schols AM, Westerterp KR, Wouters EF. (1997b). Total daily energy expenditure relative to resting energy expenditure in clinically stable patients with COPD. Thorax, 52: 780-785.

Cohen J. (1988). Statistical Statistical Power Analysis for the Behavioral Sciences, 2nd edn. New Jersey: Laurence Erlbaum.

Creutzberg EC, Schols AM, Bothmer-Quaedvlieg FC, Wouters EF. (1998). Prevalence of an elevated resting energy expenditure in patients with chronic obstructive pulmonary disease in relation to body composition and lung function. Eur. J. Clin. Nutr, 52: 396-401. MEDLINE

Department of Health . (1991). Dietary Reference Values for Food, Energy and Nutrients for the United Kingdom. London: HMSO.

Dore MF, Laaban JP, Orvoen-Frija E, Kouchakji B, Joubert M, Rochemaure J. (1997). Role of the thermic effect of food in malnutrition of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med, 155: 1535-1540. MEDLINE

Elia M. (1991). Energy equivalents of CO₂ and their importance in assessing energy expenditure when using tracer techniques. Am. J. Physiol, 260(1 Pt 1): E75-88. MEDLINE

Elia M. (1995). Changing concepts of nutrient requirements in disease: implications for artificial nutritional support. Lancet, 345: 1279-1284. MEDLINE

Elia M. (1997). Tissue distribution and energetics in weight loss and undernutrition. In Physiology, Stress and Malnutrition: Functional Correlates and Nutritional Intervention, ed. JM Kinney & HN Tucker. 383-412., New York: Lipcott-Raven.

Elia M, Jebb SA. (1992). Changing concepts of energy requirements in critically ill patients. Curr. Med. Lit. in Clin. Nutr, 1: 35-38.

Elia M, Livesey G. (1992). Energy expenditure and fuel selection in biological systems: the theory and practice of calculations based on indirect calorimetry and tracer methods. World Rev. Nutr. Diet, 70: 68-131. MEDLINE

Elia M, Jones MG, Jennings G, Poppitt SD, Fuller NJ, Murgatroyd PR, Jebb SA. (1995). Estimating energy expenditure from specific activity of urine urea during lengthy subcutaneous NaH₁₄CO₃ infusion. Am. J. Physiol, 269(1 Pt 1): E172-182. MEDLINE

Elia M, Ritz P, Stubbs RJ. (2000). Energy expenditure in the elderly. Eur. J. Clin. Nutr, 54: (Suppl 3) S1-S12.

Folgering H, Rooyackers J. (1998). Pulmonary rehabilitation in chronic obstructive pulmonary disease. Eur. Respir. J, 11: 520-523. MEDLINE

Fuller NJ, Sawyer MB, Coward WA, Paxton P, Elia M. (1996). Components of total energy expenditure in free-living elderly men (over 75 y of age): measurement, predictability and relationship to quality-of-life indices. Br. J. Nutr, 75: 161-173. MEDLINE

Gibney E, Elia M, Jebb SA, Murgatroyd P, Jennings G. (1997). Total energy expenditure in patients with small-cell lung cancer: results of a validated study using the bicarbonate-urea method. Metabolism, 46: 1412-1417. MEDLINE

Gray-Donald K, Gibbons L, Shapiro SH, Macklem PT, Martin JG. (1996). Nutritional status and mortality in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med, 153: 961-966. MEDLINE

Green JH, Muers MF. (1991). The thermic effect of food in underweight patients with emphysematous chronic obstructive pulmonary disease. Eur. Respir. J, 4: 813-819. MEDLINE

Hugli O, Frascarolo P, Schutz Y, Jequier E, Leuenberger P, Fitting JW. (1993). Diet-induced thermogenesis in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis, 148: (6 Pt 1) 1479-1483. MEDLINE

Hugli O, Schutz Y, Fitting JW. (1996). The daily energy expenditure in stable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med, 153: 294-300. MEDLINE

Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. (1999). Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med, 160: 1856-1861. MEDLINE

Leijssen DP, Elia M. (1996). Recovery of 13CO₂ and 14CO₂ in human bicarbonate studies: a critical review with original data. Clin. Sci. (Colch.), 91: 665-677. MEDLINE

Paton NI, Elia M, Jebb SA, Jennings G, Macallan DC, Griffin GE. (1996). Total energy expenditure and physical activity measured with the bicarbonate-urea method in patients with human immunodeficiency virus infection. Clin. Sci. (Colch), 91: 241-245. MEDLINE

Ryan CF, Road JD, Buckley PA, Ross C, Whittaker JS. (1993). Energy balance in stable malnourished patients with chronic obstructive pulmonary disease. Chest, 103: 1038-1044. MEDLINE

Schols AM, Soeters PB, Dingemans AM, Mostert R, Frantzen PJ, Wouters EF. (1993). Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am. Rev. Respir. Dis, 147: 1151-1156. MEDLINE

Stratton RJ, Elia M. (1999). A critical systematic analysis of the use of oral nutritional supplements in the community. Clin. Nutr, 18: (Suppl 2) 29-84. MEDLINE

Tiep BL. (1997). Disease management of COPD with pulmonary rehabilitation. Chest, 112: 1630-1656. MEDLINE

Wilson DO, Donahoe M, Rogers RM, Pennock BE. (1990). Metabolic rate and weight loss in chronic obstructive lung disease. J. Parenter. Enteral Nutr, 14: 7-11.

Woo J, Ho SC, Donnan SP, Swaminathan R. (1988). Nutritional status of healthy, active, Chinese elderly. Br. J. Nutr, 60: 21-28. MEDLINE

Table 1 The demographic and anthropometric data in COPD patients

Table 2 Measurements of energy expenditure in patients with COPD

Table 3 Total daily energy expenditure (TEE) and its components and nitrogen and energy balances