ENERGY EXPENDITURE IN EXTREMELY LOW BIRTH WEIGHT INFANTS NEAR TIME OF HOSPITAL DISCHARGE

Abstract

Objective

To test the hypothesis that total energy expenditure would be significantly higher in ELBW infants near discharge compared with healthy term infants.

Study design

This study was designed to determine total energy expenditure and body composition in a group of ELBW infants nearing discharge on full volume enteral feedings of fortified breast milk or post-discharge formula (Neosure™) (n=10, birth weight 0.8±0.1kg, gestation 26±0.8 wk, age at study 68±9 d, postconceptional age 36±1wk) and compare them with healthy term newborns all receiving breast milk (n=14, birth weight 3.5±0.5 kg, gestation 39.0±1.4 wk, age at study 2.3±1 d). Body composition and total energy expenditure were measured using the doubly labeled water method over a 7 day period.

Results

The total energy expenditure for ELBW infants was significantly higher than in term infants (89±22 kcal/kcal/kg/day vs. 58±19 kcal/kg/d (p≤0.001)). Total energy expenditure normalized to fat free mass was also significantly greater in ELBW infants (98±3 kcal/kg/d compared with 73±20 kcal/kg/d (p ≤0.01)).

Conclusions

Rates of total energy expenditure in ELBW infants nearing discharge are greater than normal healthy term infants. Higher energy intakes in the ELBW infants compensated for the higher rates of total energy expenditure in the ELBW infants.

The survival rate for ELBW infants (birth weight less than 1000 g) has dramatically improved over the last fifteen years. However, the growth of these infants, both before and after hospital discharge, remains a problem. A large majority of ELBW infants experience significant growth restriction during their stay in the NICU, and about half of these infants will remain growth-restricted at 18 months (1–3). The specific factors responsible for impaired growth in these infants are not well understood. In particular, the nutrient requirements of these infants, especially at the time of discharge, have not been determined.

A recent study has demonstrated that moderately preterm infants (~33 wks gestation) at term have somewhat higher rates of energy expenditure and requirements than normal full term infants (4). This raises the possibility that total energy expenditure and energy requirements may be substantial in ELBW infants nearing discharge.

The purpose of this study was to determine total energy expenditure using the doubly labeled water method in ELBW infants nearing discharge (34 to 38 weeks post-conceptional age, 7 to 11 weeks postnatal age) and compare them with healthy term newborns all receiving breast milk. We hypothesized that total energy expenditure would be significantly higher in these ELBW infants compared with healthy term infants.

METHODS

Subjects

The study population consisted of ELBW infants and normal healthy full term infants. Infant characteristics are noted in Table I. The ELBW infant group included 10 infants with gestational ages between 23 and 27 weeks gestation and birth weights less than 1000 g. The study was conducted at 34 to 38 weeks post-conceptional age (7 to 11 weeks postnatal age). At the time of the study, the infants were on full-volume feedings of either post-discharge formula or fortified breast milk and had been on full-volume feeds for at least 2 weeks prior to study. All infants were in open cribs. Five of the infants were on low concentrations of supplemental oxygen (~25%) for a clinical diagnosis of mild chronic lung disease at the time of the study. The other five infants had no oxygen requirement at time of study.

Table 1.

ELBW and Term infants at birth and at study. Estimated gestational age at birth (EGA), birth weight (BW), post-conceptional age (PCA).

Group	EGA (wks)	Bwt (kg)	Bwt percentile	Age (days old at study)	PCA (wks)	Study wt (kg)	Study wt percentile
ELBW	26±1	0.8±0.1	33±12	68.2±9	36±1	2.0±0.2	8±3
Term	39±1	3.5±0.5	55±31	2.3±1	N/A	3.4±0.5	60±30

The healthy term infant group included 14 subjects with gestational age greater than 37 weeks. At the time of the study, the term infants were all breast fed. Exclusion criteria for both groups included small for gestational age, and congenital or chromosomal abnormalities. This study was approved by the Institutional Review Board of Indiana University-Purdue University at Indianapolis, and informed consent was obtained from the infants’ parents or legal guardians before initiation of the study.

Anthropometry

Caloric intakes were recorded daily for infants in the ELBW infant group. Respiratory support was also recorded throughout the study period. Weights of the infants in both groups were obtained at the beginning and the end of the study and weight was measured to the nearest gram. The weight percentile was determined using the Fenton growth chart (5).

Energy Expenditure

Total energy expenditure was determined in both groups by using the doubly labeled water method over a 7-day period (6–9). The doubly labeled water (DLW) method is a non-invasive technique using stable isotopes of deuterium (²H₂) and ¹⁸O to measure total energy expenditure over time. Tracer doses of deuterium-labeled water and ¹⁸O-labeled water are administered simultaneously. The tracers become distributed throughout the entire body water over a short time (approx 4hrs). The concentrations of the deuterium and ¹⁸O labels in water are then measured in urine. Over time the labels are lost from the body. The deuterium label is lost as water from urine excretion and evaporation. The ¹⁸O label is lost in water also, however, because of the action of carbonic anhydrase, some of the ¹⁸O is incorporated into carbon dioxide and is excreted via respirations. The difference between the decay rates of deuterium and ¹⁸O isotopes reflects net carbon dioxide production. With the measured rate of carbon dioxide production and an assumed RQ, energy expenditure can be determined.

On day #1 of the study, a baseline urine sample was obtained and an oral dose of DLW was given. Urine samples were collected over the next 24 hours to measure total body water pool size. Daily urine samples were collected over the next 7 days to measure elimination rates of ²H₂ and ¹⁸O. On the last day of each DLW period, a second dose of ²H₂ was given and serial urine samples were collected for 24 hours to measure any changes in total body water. Total body water is determined from the dilution of the isotopes in the body water pool. Once the total body water pool size and respiratory quotient are known, energy expenditure can be calculated. Total body water was used to calculate the fat free mass for each infant. All urine samples were collected with cotton balls placed in the diaper with date and time of collection recorded. Samples were prepared for isotopic analysis using standard vacuum techniques and isotopic enrichment measured by isotope ratio mass spectrometry.

Energy Intake

Daily energy intake data was calculated from medical records for the ELBW. Energy intake reported is the mean intake for the seven day study period. Energy intake for the term control group was calculated by the deuterium isotope dilution method as previously described (7,8).

Calculations

Total body water was calculated from the dilution spaces of both deuterium and ¹⁸O as we have previously described (7).

The rate of CO₂ production (rCO₂) in mole/day was calculated by the following (9):

$$\mathrm{r}\mathrm{C}{\mathrm{O}}_2=0.46\times \text{Total}\text{Body}\text{Water}\times (1.01{\mathrm{k}}_{18}-1.04{\mathrm{k}}_2)$$

Where total body water (kg) is total body water mass and k₁₈ and k₂ are the calculated elimination rates of ¹⁸O and deuterium, respectively. The rCO₂ is then converted to total daily energy expenditure in kcal/day using the Weir equation (10).

$$\text{Total}\text{Energy}\text{Expenditure}=22.4\times (\mathrm{1.1.}\mathrm{r}\mathrm{C}{\mathrm{O}}_2+3.94\mathrm{r}{\mathrm{O}}_2)-2.17\times {\mathrm{U}}_{\mathrm{N}}$$

Where rO₂ is calculated from the food quotient of the diet, and U_N is the 24 hour urinary nitrogen excretion in grams. In practice, the contribution from the last term is minor and can be ignored.

Lean body mass was calculated from total body water (7). Fat mass was determined as the difference between body weight and lean body mass.

Statistics

Results were compared using analysis of variance (ANOVA). Data are expressed as mean ± SD.

RESULTS

Weight gain over the study period was significantly higher for the ELBW infants compared with the term infants (34±11 g/d vs 13±27 g/d; p<0.05). All ELBW infants gained weight over the study period, whereas 2 term infants lost weight. The body composition in the ELBW infants had a lower fat mass % and a higher lean mass % than the term infants (Table II). Total energy expenditure in ELBW infants is significantly higher at 89±22 kcal/kg/d (p≤0.001) compared with total energy expenditure in term infants at 58±19 kcal/kg/d (Figure). When corrected for fat free mass, the total energy expenditure remains significantly higher (p ≤0.01) in the ELBW infant group (98±28 kcal/kg_{fat free mass}/d compared with 73±20 kcal/kg_{fat free mass}/d). Parallel to the higher rates of total energy expenditure, energy intake for ELBW infants was significantly higher than the term infants (127±17 kcal/kg/d vs 80±28 kcal/kg/d p<0.0005).

Table II.

Group	Total Body Water %	Fat Free Mass (g)	Fat Mass (g)	% Fat	% Fat Free Mass
ELBW	73±9*	1.98±0.2*	0.17±0.2*	7.3*	92.7*
Term	63±7	2.72±0.5	0.68±0.3	19.8	80.2

Figure.

Total energy expenditure per kg and total energy expenditure per kg fat free mass in ELBW and Term infants. Black bars represent ELBW infants and gray bars represent Term infants. *p≤0.01.

The apparent energy balance was estimated by energy intake minus total energy expenditure. These are approximate values because there were no corrections made for stool or urine losses. The apparent energy balance for ELBW infants is higher at 37±27 kcal/kg/d compared with 22±26 kcal/kg/d for term infants, however, this difference is not statistically significant. This may be a type II error, and it is possible that the ~15 kcal/kg/d difference in apparent energy balance between the 2 groups contributed to the different growth rates.

DISCUSSION

In the present study, total energy expenditure was determined over a 7 day period in ELBW infants nearing hospital discharge (~36 weeks post-conceptional age) and in normal term infants. Total energy expenditure was approximately 55% higher in ELBW infants nearing hospital discharge compared with normal term infants. Higher energy intakes were able to compensate for higher rates of energy expenditure in ELBW infants, and the ELBW infants achieved a greater rate of weight gain during the study.

Total energy expenditure was measured by the doubly labeled water method, a non-invasive technique that has been extensively validated in a variety of populations and clinical circumstances (11–13). This method has been applied by our group and others to assess energy metabolism in normal and premature infants, as well as in infants with congenital heart disease and cystic fibrosis (7,8,14–17). Total energy expenditure values obtained in the normal term infants in the present study (~60kcal/kg/day) are similar to previously reported determinations (5,14). Olhager and Forsum measured total energy expenditure in moderately preterm infants at term post-conceptional age and in normal full term infants. Total energy expenditure in these moderately preterm (~32 weeks gestation at birth) at term was significantly higher (~23%) than total energy expenditure in normal full term infants (5). This is consistent with the findings of the present study, although the ELBW infants (~26 weeks gestation at birth) studied have total energy expenditure rates ~ 20% higher than that reported in moderately premature infants at term.

The mean weight of the ELBW infants at study was less than the 10^th percentile suggesting suboptimal growth from birth; poor growth of ELBW infants in the NICU is common and has been well documented (1,2). A significantly lower fat mass and a higher proportion of lean body mass is consistent with this growth pattern, and suggests a nutritional deficit. However, differences in body composition between ELBW infants and term infants does not completely explain the differences in total energy expenditures between the two groups, as total energy expenditure normalized to lean body mass remains significantly higher in ELBW infant group.

Uthaya et al recently measured adiposity in preterm infants at term using whole body magnetic resonance (18). In this group of former ~29 wk gestation, 1.2 kg infants, total adiposity was similar to term infants, but intraabominal adipose tissue was increased. The ELBW infants of the present study (~26 wk gestation, 800g bwt) were smaller both at birth and at the time of study, and clearly have reduced fat mass compared with term infants. Although intraabdominal adipose tissue was not measured with the techniques used in the present study, it is possible that intraabominal adipose tissue in these ELBW infants may be similar or even increased compared with term infants.

A potential confounding factor, in the present study, is the oxygen requirement in 5 of the 10 ELBW infants at the time of total energy expenditure measurement. Increased energy expenditure has been measured in some but not all studies of premature infants with chronic lung disease (19,20). However, the inclusion of ELBW infants with an oxygen requirement does not completely account for the increased total energy expenditure in this group. If the infants requiring oxygen are excluded from analysis, total energy expenditure remains significantly higher in the ELBW infants at term (82 ± 18 kcal/kg/d vs. 58 ± 19 kcal/kg/d, p < 0.05).

It is unclear at present why ELBW infants at term gestation have higher rates of total energy expenditure. It is possible that ELBW infants have a higher degree of physical activity than normal term infants, although this seems unlikely. Perhaps a more plausible explanation is the energy cost of growth. The rate of weight gain in ELBW infants was significantly higher than term infants over the study period; the energy costs of synthesizing new body tissues are substantial, and are likely to make a significant contribution to higher rates of total energy expenditure, as suggested by other investigators (5,21). It is also possible that thermal stresses in ELBW infants may play a role in higher rates of total energy expenditure.

In summary, rates of total energy expenditure in ELBW infants nearing discharge are greater than normal healthy term infants. These higher rates of total energy expenditure must be considered when choosing nutritional support; an intake of ~ 120kcal/kg/day in these ELBW infants at term appears to compensate for higher rates of total energy expenditure and produces a reasonable growth rate and energy balance. Currently it is unknown how long high rates of total energy expenditure might persist in ELBW infants. Obtaining this information will be important to provide optimal nutritional support to these infants after hospital discharge.

Abbreviations

ELBW

Extremely low birth weight

EGA

Estimated gestational age

EB

Energy balance

BW

Birth weight