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3. Results

3.1. Relationship between total energy expenditure and body weight
3.2. Construction of centiles

Table 1 shows a number of the demographic characteristics of the infants recruited for the major study. The means and standard deviations of age, length and weight are shown in Table 2 and the means and standard deviations for total energy expenditure are shown in Table 3. Dose loss, caused by posseting or vomiting during or immediately following the administration of the dose resulted in a loss of 2,1 and 4 data points at periods A, B and C, respectively. The mean and standard deviation of the isotopic enrichments in the predose urine samples, the disappearance rate constants Ko and Kd and the intercepts of the regression lines of log enrichment versus time are shown in Table 4.

Table 1. Some demographic characteristics of the infants recruited into the study

Table 2. Means and standard deviations of age, weight and length of the infants studied

Table 3. Means and standard deviation of total energy expenditure expressed kJ/d and kJ/kg per day

Table 4. Predose isotope enrichments, rate constants (kd, ko) and intercepts of the regression lines for the cohort of full-term infants studied

3.1. Relationship between total energy expenditure and body weight

The regression coefficients and intercept obtained from the regressions of logEE and logWt are given in Table 5. In the first analysis, the individual regression coefficients at each period were not significantly different (variance ratio = 0.2 on 2 and 130 df). This led to the second analysis, where the regression coefficients for each period were constrained to be the same, but with different intercepts. The intercepts were significantly different (variance ratio = 5.6 on 2 and 132 df), showing that after adjustment of weight, there remained an important age effect.

Table 5. Intercepts, regression coefficients and standard errors from the regression of logEE on logWt at three periods of age. In Analysis 1 the periods are treated separately, while in Analysis 2 the regression coefficients for each period are constrained to be the same

The average regression coefficient for the relationship between log body weight and log energy expenditure of 0.56 (SE = 0.22) is significantly different both from 0 and from 1. A regression coefficient of 0 would have indicated that energy expenditure was not related to body weight at all, whilst a regression coefficient of 1 would indicate that an adjustment to kcal or kJ/kg body weight was appropriate to remove the body weight effect upon energy expenditure. Conversely, the average regression coefficient of 0.56 is very close to 0.50, which indicates that a numerically convenient and statistically valid adjustment of energy expenditure in early infancy would be to express energy expenditure as kcal/kg^0.5 or kJ/kg^0.5, that is per square root of body weight.

3.2. Construction of centiles

Centiles were calculated by the LMS method for total energy expenditure expressed as kJ/d, kJ/kg per day and per day. The centile charts are shown in Figures 1 to 3, respectively.

4. Discussion

We have used the doubly labelled water technique to measure non-invasively total energy expenditure over a period of 7 days, to provide the first centiles for total energy expenditure for infants up to 6 months of age.

There are a number of potential sources of error in the doubly labelled water technique that need careful consideration. These include the choice of the respiratory quotient (RQ), and the proportion of water output fractionated, the possible sequestration of isotope into body tissue, and the effect of weaning, or major changes in diet during an isotope study period.

In adult studies, using the doubly labelled water technique, an RQ of 0.85 is usually applied. Although RQ may vary throughout a study, over a period of 10-14 days, the length of most adult studies, RQ will tend towards 0.85 and the use of this figure will not introduce a large error. However, an RQ value used in infants must take into account growth. BLACK et al. (1986) list unadjusted and adjusted food quotients (FQ) for infants, and conclude that the FQ and RQ can be used interchangeably in the doubly labelled water technique, due to the length of study period (7 days in our study). The value for RQ we have used at periods A and B (i.e., 0.87) is the mean of some 143 individual calculations of FQ, adjusted to allow for growth using the body composition data reported by FOMON (1974). At period C an adjusted FQ of 0.855 is used; this is based on 253 individual measurements of FQ between the ages of 4 and 12 months. Consequently, we feel that our choice of RQ is appropriate and justified.

Another source of potential error in the doubly labelled water technique is the use of an inappropriate value for the proportion of total water output that is subject to isotopic fractionation (fractionation factor). The magnitude of error produced in the final estimation of total energy expenditure due to an inappropriate choice of fractionation factor depends strongly on the kd:ko ratio. The closer this ratio is to 1 the greater the final error. In adults, the kd:ko ratio is usually about 0.75. In young infants, as water turnover is high in relation to carbon dioxide production rate, the ratio is higher (0.86, 0.85, and 0.82 at periods A, B and C, respectively, in this study). COWARD (1988) recently showed that with a kd:ko ratio of 0.90 as much as an 8% error in carbon dioxide production rate will be induced by an error of 0.1 in the value of fractionation factor used. The factor assumed in this present study (0.13) is based upon an unpublished water balance study (LUCAS, unpublished results), in a subset of infants in the present cohort.

In the validation study reported by JONES et al. (1987) a higher value (0.18) was used. This value was based upon the assumptions that breath is saturated with water and contains 3.5% carbon dioxide. Thus, breath water losses can be related to carbon dioxide production rate. Skin losses (non-sweat) were estimated using a value of 0.18 g/min/m2 insensible skin water loss, and assuming that 75% of the infants' skin was exposed to the air. While appropriate for the infants studied by JONES et al. (1987), their assumed value for the proportion of exposed skin was undoubtedly too high for the infants in our study. We estimate that a figure of about 30% would be more appropriate. Using this, and the approach of JONES et al. (1987), the mean proportion of water output fractionated in our study would have been 0.15; close to our value of 0.13.

The sequestration of isotope into tissues during the rapid growth experienced in early infancy could lead to error in the calculation of total energy expenditure. Labelled hydrogen exchanges with non-aqueous hydrogen in proteins and other tissues. In contrast, there is little non-aqueous oxygen in the body with which ¹⁸O could exchange, and in any case such an exchange does not occur readily at physiological temperature and pH, JONES et al. (1987) addressed the potential problem of label sequestration in rapidly growing infants. They hypothesised that if there was significant isotope sequestration, notably of labelled hydrogen, the difference in energy expenditure (calculated by doubly labelled water) and respiratory gas exchange would be correlated with the change in body weight during the study period. No such relationship was found and these workers concluded that sequestration rates were insignificant.

Finally, changes in the enrichment of ²H and ¹⁸O in dietary water during a study period can produce major error in the calculation of energy expenditure with doubly labelled water (ROBERTS et al., 1988a; JONES et al., 1988). During infancy the principal factor in the change in dietary water ²H and ¹⁸O content is weaning. At periods A and B. the infants studied here were exclusively being breast- or formula-fed, while at period C, care was taken that no major change in diet occurred during the study period.

We have attempted to define the most appropriate way that an infant's energy expenditure should be expressed in relation to body weight in order to minimize the correlation between body weight and energy expenditure. We have found that a statistically valid and numerically convenient adjustment of energy expenditure would be to express energy expenditure as kcal/kg^0.5 or kJ/kg^0.5, that is, per square root of body weight. We suggest that in studies on energy metabolism in early infancy this expression should be used.

References

BEAL, V.A.: Nutritional intake. In: Human Growth and Development, R.W. McCANNON (Ed.). Charles C. Thomas, Springfield, Illinois, IL, 1970.

BLACK, A.E., PRENTICE A.M., COWARD W.A.: use of food quotients to predicted respiratory quotients for the doubly-labeled water method of measuring energy expenditure. Hum. Nutr.: Clin. Nutr., 40C, 381-391 (1986).

BOX, G.E.P., COX, D.R.: An analysis of transformations. J.R. Statist. Soc. B., 26, 211-252 (1964).

COLE, T.J.: Fitting smoothed centile curves to reference data. J.R. Statist. Soc. A., 151, 385-418 (1988).

COWARD, W.A.: The doubly-labelled water (²H₂¹⁸O) method: principles and practice. Proc. Nutr. Soc., 47, 209-218 (1988).

DAVIDSON, S., PASSMORE, R., BROCK, J.F.: Human Nutrition and Dietetics. Churchill LIVINGSTONE London, 1973.

DEPARTMENT of HEALTH and SOCIAL SECURITY: Recommended daily amounts of food energy and nutrients for groups of people in the United Kingdom. Report on Health and Social Subjects No. 15. H.M. Stationery office, London, 1979.

FLEISCH, A.: Le métabolisme basal standard et sa détermination au moyen du 'Métabocalculator'. Helv. Med. Acta., 18, 23 (1951).

FOMON, S.J.: Infant Nutrition, 2nd. ed. W.B. Saunders Co., Philadelphia, PA, 1974.

JONES, P.J.H., WINTHROP, A.L., SCHOELLER, D.A., FILLER, R.M., SWYER, P.R., SMITH, J., HEIM, T.: Evaluation of doubly-labelled water for measuring energy expenditure during changing nutrition. Am. J. Clin. Nutr., 47, 799-804 (1988).

JONES, P.J.H., WINTHROP, A.L., SCHOELLER, D.A., SWYER, P.R., SMITH, J., FILLER, R.M. HEIM, T.: Validation of doubly-labelled water for assessing energy expenditure in infants. Pediatr. Res., 21, 242-246 (1987).

OWEN, O.E., HOLUP, J.L., D'ALESSIO, D.A., CRAIG, E.S., POLANSKY, M., SMALLEY, K.J., KAULE, E.C., BUSHMAN M.C., OWEN L.R. MOZZOLI, M.A., KENRICK Z.V. BODOEN, G.H.: A reappraisal of the calorific requirements of man. Am. i. Clin. Nutr., 46, 875-885 (1987).

ROBERTS, S.B., COWARD, W.A., SCHLINGENSEIPEN, K.H., NOHRIA, V., LUCAS, A.: Comparison of the doubly-labelled water (²H₂¹⁸O) method with indirect calorimetry and a nutrient balance study for simultaneous determination of energy expenditure, water intake and metabolizable energy intake in preterm infants. Am. J. Clin. Nutr., 44, 315-322 (1986).

ROBERTS, S.B., COWARD, W.A., EWING, G., SAVAGE, J., COLE, T.J., LUCAS, A.: Effect of weaning or accuracy of doubly-labelled water method in infants. Am. J. Physiol., 254, R622-R627 (1988a).

ROBERTS, S.B., SAVAGE. J., COWARD, W.A., CHEW, B., LUCAS, A.: Energy expenditure and intake in infants born to lean and overweight mothers. New Engl. J. Med., 318, 461-466 (1988b).

SHEPHERD, R.W., HOLT, T.L., VASQUEZ-VELASQUEZ, L., COWARD, W.A., PRENTICE, A., LUCAS, A.: Increased energy expenditure in young children with cystic fibrosis. Lancet, i. 1300-1303 (1988).

WEIR, J.V. de V.: New method for calculating metabolic rate with special reference to protein metabolism. J. Physiol., 109, 1-9 (1949).

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Discussion summarized by J.V.G.A. Durnin

It was doubted that the reference Wt^0.5 (i.e., body weight to the power of 0.5 = square root of body weight) had any usefulness in human infancy and childhood. It was pointed out that this power of Wt is affected by the growth of bone, fat, etc., and the influence of these tissues would alter at different growth periods.

Also, there are problems about the use of the same factor of Wt (e.g., energy per kg body weight) or of fat-free mass for well-nourished or undernourished infants, since both body composition and growth rates differ in these groups.

Davies et al. suggested that the data collected using the doubly-labelled water technique on Cambridge populations might be useful as reference data. This may not be appropriate since data from upper-class Cambridge women and children may not be representative of other population groups.

The doubly-labelled water method of measuring energy expenditure does not permit any breakdown of activity patterns but nevertheless is a way of measuring total energy expenditure of free-living infants and children. It might be possible to combine this with heart-rate measures to allow some qualitative assessment of physical activity patterns.

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