Effects of quality of energy on substrate oxidation in enterally fed, low-birth-weight infants

¹ From the Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Babies and Children's Hospital, College of Physicians and Surgeons, Columbia University, New York.

² Reprints not available. Address correspondence to S Kashyap, Department of Pediatrics, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032. E-mail: sk48{at}columbia.edu.

ABSTRACT  
Background: Carbohydrate and fat may differ in their ability to support energy-requiring physiologic processes, such as protein synthesis and growth. If so, varying the constituents of infant formula might be therapeutically advantageous.

Objective: We tested the hypothesis that low-birth-weight infants fed a diet containing 65% of nonprotein energy as carbohydrate oxidize relatively more carbohydrate and relatively less protein than do infants fed an isoenergetic, isonitrogenous diet containing 35% of nonprotein energy as carbohydrate.

Design: Sixty-two low-birth-weight infants weighing from 750 to 1600 g at birth were assigned randomly and blindly to receive 1 of 5 formulas that differed only in the quantity and quality of nonprotein energy. Formula containing 544 kJ•kg^-1•d^-1 with either 50%, 35%, or 65% of nonprotein energy as carbohydrate was administered to control subjects, group 1, and group 2, respectively. Groups 3 and 4 received gross energy intakes of 648 kJ•kg^-1•d^-1 with 35% and 65% of nonprotein energy as carbohydrate. Protein intake was targeted at 4 g•kg^-1•d^-1. Substrate oxidation was estimated from biweekly, 6-h measurements of gas exchange and 24-h urinary nitrogen excretion.

Results: Carbohydrate oxidation was positively (r = 0.71, P < 0.0001) and fat oxidation was negatively (r = –0.46, P < 0.001) correlated with carbohydrate intake. Protein oxidation was negatively correlated with carbohydrate oxidation (r = –0.42, P < 0.001). Fat oxidation was not correlated with protein oxidation. Protein oxidation was less in infants receiving 65% of nonprotein energy as carbohydrate than in groups receiving 35% nonprotein energy as carbohydrate.

Conclusion: These data support the hypothesis that energy supplied as carbohydrate is more effective than energy supplied as fat in sparing protein oxidation in enterally fed low-birth-weight infants.

Key Words: Low-birth-weight infants • substrate oxidation • oxygen consumption • carbon dioxide production • respiratory quotient • energy expenditure • nonprotein energy

INTRODUCTION  
The current goal of nutritional management of preterm infants, as recommended by the American Academy of Pediatrics (1), is to achieve a postnatal growth approximating that of a normal fetus of the same postconceptional age. Although rates of weight gain similar to or greater than the intrauterine rate have been achieved by feeding preterm infants enriched diets (2–6), invariably, these diets lead to a disproportionate increase in body fat. The reasons for this postnatal failure to maintain the high fetal rates of protein synthesis relative to fat deposition are not known. One difference between fetal and neonatal life is the relatively greater dependence of the fetus on carbohydrate rather than fat as a source of energy. If the fetus is relatively more dependent on carbohydrate than fat, then it is possible that the same is true of infants of comparable maturity after birth. There is some evidence that, joule for joule, use of carbohydrate as an energy source is more effective in supporting protein accretion than use of fat (7–10). There are investigators, however, who assert that this effect is transient (11). This hypothesis remains untested in enterally fed, low-birth-weight (LBW) infants. Should there be significant differences in the growth-supporting effects of fat and carbohydrate, these differences might be exploited in the design of formulas for premature infants and human milk supplements.

Many studies have investigated the effect of varying the source of nonprotein energy on substrate use in parenterally fed, newborn infants (12, 13). However, the consequences of variations in the quality of nonprotein energy have not been investigated in enterally fed, preterm infants. In adults, substrate oxidation is dependent on the relative proportions of carbohydrate and fat in the diet (14, 15). The purpose of the present study was to test the hypothesis that LBW infants fed diets containing 65% of nonprotein energy as carbohydrate oxidize relatively more carbohydrate and relatively less protein than do infants fed isoenergetic, isonitrogenous diets containing 35% nonprotein energy as carbohydrate.

SUBJECTS AND METHODS  
Experimental design
LBW infants without gastrointestinal, renal, or severe pulmonary disease and who weighed between 750 and 1600 g at birth were stratified by birth weight into 1 of 3 ranges: 750–1000, 1001–1300, or 1301–1600 g. The infants were then randomly assigned by a blind draw to receive 1 of 4 experimental formulas or a control formula. All formulas were designed to provide protein intakes of 4 g•kg^–1•d^–1 when fed at 180 mL•kg^–1•d^–1. The control formula and formulas 1 and 2 were designed to provide 502 kJ•kg^–1•d^–1 when fed at the same volume. The carbohydrate and fat contents of the formulas were varied to provide 35% of nonprotein energy as carbohydrate in formula 1, 65% of nonprotein energy in formula 2, and 50% of nonprotein energy in the control formula. Formulas 3 and 4 were designed to provide higher energy intakes of 628 kJ•kg^-1•d^–1 when fed at 180 mL•kg^–1•d^–1, with nonprotein energy as 35% and 65% from carbohydrate. All formulas were made specifically for this study by Ross Laboratories (Columbus, OH). Formula bottles were number coded and the investigators were not informed of the code until the study was completed. The protein content of the formulas was modified bovine milk protein with a ratio of whey protein to casein of 60:40. The carbohydrate content of the formulas was composed of equal amounts of lactose and corn syrup solids, and fat was provided as a mixture of coconut, soy, and safflower oils. The electrolyte, mineral, and vitamin contents of the formulas were similar and met recommended dietary intakes (1). The measured energy content of the formulas were slightly higher than what was planned in the study design. The actual macronutrient intakes of the 5 groups are shown in Table 1. Protein concentrations in the specially designed formulas varied, which resulted in a slightly lower absolute protein intake by the infants randomly assigned to group 4 than in infants in group 3.

View this table:
TABLE 1. Dietary intakes of study groups¹  
The study was approved by the Institutional Review Board of the College of Physicians and Surgeons of Columbia University. Written, informed parental consent was obtained before infants were enrolled in the study.

Experimental protocol
Shortly after enrollment and as soon as medically permitted, the infants were transferred to the General Clinical Research Center, where they remained until discharge. The assigned formula was administered as soon as enteral feedings could be tolerated by the infant. The volume of the formula was increased as tolerated until the desired intake of 180 mL•kg^–1•d^–1 was achieved. This volume was then maintained throughout the study until the infant's weight reached 2200 g or until the infant was discharged from the hospital. During this time, infants were cared for in servo-controlled, single-walled incubators under thermoneutral conditions. The formulas were administered either by orogastric tube or, if tolerated, by nipple. Vitamin E [25 mg (25 IU)] and a mixture of vitamins A [450 µg (1500 IU)], C (35 mg), and D [10 µg (400 IU)] were administered daily once feedings were established. The volume of formula intake, nitrogen excretion, oxygen consumption ( Measurement of gaseous metabolism
Once infants had been receiving full enteral feedings for 72 h, gaseous metabolism was measured every 2 wk until discharge. Each study began immediately after the feeding at 0800, was interrupted for the 1100 feeding, and then continued until the infant was ready for the 1400 feeding. Data from 150 consecutive minutes were collected during each interfeed period.

Offline processing with special purpose software was used to correct the raw digital data for drift, transform the data using the appropriate calibration standards, correct measurements to standard temperature and pressure, correct the flow for differences in respiratory exchange, and integrate the signals on a continuous minute-to-minute basis. Measurements of Studies were conducted every 2 wk. Of the 62 infants, 46 participated in 2 studies, 11 participated in 3 studies, and 5 infants participated in 1 study. Measurements for each infant were then averaged to yield a single estimate of Urinary nitrogen excretion
Seventy-two–hour urine collections spanning the measurements of gaseous metabolism were obtained every 2 wk. The methods used for collecting and analyzing urinary nitrogen excretion were described previously (3). The mean urine volume was slightly but significantly less in the infants receiving the higher-energy diets (111 ± 7.3, 110 ± 7.6, and 108 ± 10.4 mL•kg^-1•d ^-1 in the control group and groups 1 and 2, and 102 ± 11.3 and 102 ± 6.5 mL•kg^-1•d ^-1 in groups 3 and 4, respectively). The variability in the urine volume within groups ranged from 6.5% to 11%. Sex did not influence the urine volume collected.

Calculation of substrate oxidation
Net substrate oxidation was calculated by using the classic theory and equations of Lusk (17, 18). The CO₂ by oxidizing protein were estimated empirically by Magnus-Levy (19). The errors that result from the assumptions about the composition of fatty acids and the quality of protein are thought to be small when the composition of dietary fat and protein does not vary appreciably (20, These equations must be interpreted differently whenever net lipogenesis from carbohydrate is known to occur (20–25). When nonprotein respiratory quotients are >1.0, ie, when net lipogenesis is thought to occur, fat oxidation is a negative value and thus, measured carbohydrate oxidation and true carbohydrate oxidation differ by the glucose equivalent of the fat synthesized. Under these conditions, true carbohydrate oxidation is less than measured carbohydrate oxidation (22, 25). It is also known that lipogenesis can occur in some tissues at a nonprotein RQ of <1.0 (22–25). Thus, the calculated carbohydrate oxidation rate represents the true carbohydrate oxidation rate, the amount of glucose converted to fat during lipogenesis, and an unknown but negligible contribution from gluconeogenesis. The equations used in the calculations (22) are listed below:

RESULTS  
Gaseous metabolism was measured in 62 of the 68 infants randomly assigned. Two infants were withdrawn from the protocol because they developed a patent ductus arteriosus requiring fluid restriction (one infant each from groups 1 and 4) and 2 were withdrawn after developing necrotizing enterocolitis (one infant each from groups 2 and 3). One infant's formula (from group 1) was inadvertently changed before the infant completed the protocol, and another infant (from group 4) completed other aspects of the study but was not measured for gaseous metabolism. All of the formulas were well tolerated by the infants. Characteristics of the study groups were not significantly different (Table 2).

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TABLE 2. Characteristics of the study population¹  
Data that summarize the bioenergetics of the study populations are shown in Table 3. As anticipated, the mean energy balances (energy stored) of infants in groups 3 and 4, ie, the high energy intake groups (648 kJ•kg^-1•d ^-1), were greater than the energy balances of infants in groups 1 and 2, the lower energy intake groups (544 kJ•kg^-1•d ^-1). Despite the higher rate of energy expenditure, the infants in group 4 who received 65% of their nonprotein energy as carbohydrate retained more energy than did the infants in group 3 who received 65% of their nonprotein energy intake as fat. At the lower energy intake there was no difference in energy expenditure between the groups. However, the infants on the high carbohydrate diet had a higher energy balance than those on the high fat formula. The groups consuming high intakes of fat (groups 1 and 3) lost more energy via excreta than did the infants with high intakes of carbohydrate (groups 2 and 4) and the infants in the control group.

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TABLE 3. Energy balance data of the study groups¹  
As anticipated, the mean
View this table:
TABLE 4. Metabolic gas exchange and urinary nitrogen excretion of the study groups¹  
The results of the substrate oxidation calculations are shown in Table 5. As expected, carbohydrate oxidation increased with carbohydrate intake. Thus, groups receiving 65% of the nonprotein energy as carbohydrate, ie, groups 2 and 4, oxidized carbohydrate at greater rates than did the groups receiving only 35% of nonprotein energy as carbohydrate (groups 1 and 3). Likewise, fat oxidation varied inversely with carbohydrate intake (r = 0.46, P < 0.001). Consistent with the hypothesis, protein oxidation at both gross energy intakes was less in groups receiving 65% of nonprotein energy as carbohydrate. The protein oxidation of the control group at an energy intake of 544 kJ•kg^-1•d ^-1 was intermediate.

View this table:
TABLE 5. Macronutrient oxidation rates of the study groups¹  
The regression relations of carbohydrate intake with both carbohydrate and fat oxidation are shown in Figure 1. As carbohydrate intake increased, carbohydrate oxidation increased (r = 0.71, P < 0.0001) and fat oxidation decreased. In this study, by design, carbohydrate and fat intake were closely related. Carbohydrate intake was a superior predictor of carbohydrate and fat oxidation. Inclusion of fat intake in the regression did not improve the regression relation. As noted above, at nonprotein RQs >1, carbohydrate oxidation included true carbohydrate oxidation and carbohydrate used in fat synthesis.

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FIGURE 1. . Regression relation of carbohydrate oxidation (n = 62; y = 4.064 + 0.601x; r = 0.71; P < 0.0001) and fat oxidation (n = 46; y = 3.676 -0.145x; r = -0.46; P < 0.001) with carbohydrate intake. At a respiratory quotient >1, the measured carbohydrate oxidation includes true carbohydrate oxidation and carbohydrate used in fat synthesis (negative fat synthesis).

 
The correlations between protein oxidation and both carbohydrate and fat oxidation are shown in Figure 2. Protein oxidation was inversely correlated with carbohydrate oxidation but was not correlated with fat oxidation.

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FIGURE 2. . Correlation of protein oxidation with carbohydrate and fat oxidation. There was a significant negative correlation between protein and carbohydrate oxidation (n = 62; r = -0.42; P < 0.001), whereas the correlation between protein and fat oxidation was not significant (n = 46; P = 0.39). Sixteen patients with a respiratory quotient 1 were not included when plotting protein against fat oxidation because there was no occurrence of net fat oxidation.

 

DISCUSSION  
Measurements of metabolic gas exchange and 72-h urinary nitrogen excretion obtained prospectively in a double-blind, randomized study of healthy, growing LBW infants were used to estimate the rates of carbohydrate, fat, and protein oxidation. The results indicate that the rate of protein oxidation is less when 65% of nonprotein energy is supplied as carbohydrate and 35% is supplied as fat than when the proportions are reversed. This was true at gross energy intakes of 544 and 648 kJ•kg^-1•d ^-1. In the infants studied, carbohydrate intake was noted to have a significant, positive relation with carbohydrate oxidation and a negative relation with fat oxidation. Protein oxidation decreased significantly as carbohydrate oxidation increased, but was not related to fat oxidation. Considered together, these data support the hypothesis that, in healthy, enterally fed LBW infants, carbohydrate is more effective than is fat in reducing the oxidation of protein.

In the present study, the higher metabolizable energy intake in the high-carbohydrate diet groups confounds the group comparison for the specific effect of quality of energy on protein oxidation. There was too little variation in metabolizable energy to permit within group analysis between metabolizable energy and protein oxidation. As expected, metabolizable energy intake of the infants correlated significantly with protein oxidation (r = 0.53, P < 0.0001). However, the effect of carbohydrate intake on protein oxidation was apparent with or without metabolizable energy as a covariate in the analysis of variance.

This decrease in protein oxidation (ie, increase in protein stores) with increasing carbohydrate intake at a constant protein intake is consistent with reports in adults of enhanced protein retention when carbohydrate is the primary energy substrate in both enteral (7, 8) and parenteral diets (9). Although greater nitrogen retention with increasing energy intake was reported in enterally fed (3, 27) and parenterally fed (28) LBW infants, knowledge regarding possible differential effects of carbohydrate compared with fat (quality of nonprotein energy) on nitrogen retention in enterally fed LBW infants has been lacking. Published reports of nonprotein energy effects on nitrogen retention are limited to parenterally fed infants, and results have been inconsistent. Investigators reported increased (10), unchanged (13, 29, 30), and decreased (12) nitrogen retention with high carbohydrate intakes. A study investigating the administration of a high-fat formula to premature infants with bronchopulmonary dysplasia reported no difference in nitrogen retention of infants receiving a high-fat compared with a high-carbohydrate diet (31). In contrast, we observed higher rates of nitrogen retention (444.1 ± 22.1 compared with 420.2 ± 23.7 mg•kg^-1•d ^-1 in groups 2 and 1, respectively, and 459.2 ± 20.4 compared with 438.7 ± 26.3 mg•kg^-1•d^-1 in groups 4 and 3, respectively) and weight gain (23.2 ± 2.9 compared with 20.2 ± 1.8 g•kg^-1•d^-1 in groups 2 and 1, respectively, and 24.9 ± 2.4 compared with 20.7 ± 2.3 g•kg^-1•d ^-1 in groups 4 and 3, respectively) in infants fed the high-carbohydrate diets at both gross energy intakes (32). However, infants fed the high-energy, high-carbohydrate diet had increased fat deposition as evidenced by the significantly greater increase in skinfold thickness (1.70 ± 0.47 compared with 0.93 ± 0.38 mm/wk in groups 4 and 3, respectively).

The direct correlation of increasing carbohydrate oxidation with increasing carbohydrate intake observed in the present study of enterally fed LBW infants has also been observed in enterally fed adults (15, 33) and parenterally fed infants (12, 13, 34). The diminished fat oxidation with increasing carbohydrate intake and the enhanced fat oxidation with increasing fat intake observed in this study was also noted in some studies (12, 14) but not in others (35, 36).

The conclusions of the present study must be interpreted in light of the study population, experimental design, experimental methodology, and assumptions made in estimating substrate oxidation rates from metabolic gas exchange and urinary nitrogen excretion. The study subjects were healthy, growing LBW infants who were receiving full enteral intakes. The dietary intervention was meticulously controlled, and the experimental protocol spanned a substantial period of time (study duration was a mean of 25 ± 9 d). We carefully validated the indirect calorimeter and defined the error in the use of 6-h studies to predict total daily gas exchange (16, 37, 38). Multiple serial measurements were obtained in most of these infants to further reduce the sampling error associated with these measurements. Among the limitations of the study design was that the diets were designed with a fixed inverse relation between carbohydrate and fat intake; thus, the carbohydrate and fat intakes were not truly independent of each other.

Although thought to be both theoretically and empirically sound, the interpretation of substrate oxidation values as measured by indirect calorimetry is sensitive to both methodologic errors and erroneous assumptions. The assumptions underlying the classic technique for calculating macronutrient oxidation from gas exchange are thought to be most secure when applied to long-term net oxidation rates (21). However, these assumptions may not hold when experimental conditions are not rigidly controlled. For example, when the sampling period is brief, the effects of potentially confounding variables, such as variations in the quality of the diet, physical activity of the infant, and changes in the physical environment (eg, temperature and humidity), need to be adequately controlled. O₂, and RQ all vary significantly depending on the time elapsed after feeding, the amount of food, and, as shown here, the composition of the food (37, 39). Thus, estimates of oxidation rates made from short periods of measurement without control of the aforementioned variables could be inaccurate. As we and others have shown, inclusion of 2 full feeding periods can eliminate most of the variability related to feeding, physical activity, and sleep state (38, This randomized, prospective investigation of the effects of carbohydrate compared with fat, when fed at 2 isonitrogenous gross energy intakes, on the substrate oxidation of enterally fed LBW infants showed a significant positive relation between carbohydrate intake and carbohydrate oxidation and an inverse relation between fat oxidation and carbohydrate intake. There was less protein oxidation at both gross energy intakes in groups receiving 65% of nonprotein energy as carbohydrate. Within the limitations of the theory and the methodology, these data support the hypothesis that carbohydrate is more effective than is fat in sparing protein oxidation in enterally fed LBW infants. However, because of the increased metabolic load of carbon dioxide and the lack of evidence for the safety of carbohydrate-enriched dietary intakes in LBW infants, particularly regarding the enhanced release of insulin when such diets are given over prolonged periods of time, recommendations for specific enrichment of preterm infant formulas with carbohydrate cannot be made without further evaluation.

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