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close this bookProtein-Energy Interactions (International Dietary Energy Consultative Group - IDECG, 1991, 437 pages)
close this folderEffects of protein-energy interactions on growth
View the document(introductory text...)
View the documentAbstract
View the document1. Introduction
Open this folder and view contents2. Mechanisms for effects of protein and energy on growth
View the document3. The determinants of catch-up growth
View the document4. Effect of the protein/energy ratio on growth of premature infants
View the document5. Effect of protein and energy on growth of children with primary malnutrition
View the document6. Effect of the P/E ratio on growth of children with malnutrition secondary to chronic renal insufficiency
View the document7. Conclusions and speculations
View the documentAcknowledgements
View the documentReferences

4. Effect of the protein/energy ratio on growth of premature infants

Premature infants, presently better defined as preterm infants born before 38 weeks of gestation, present an interesting model to assess effects of protein and energy intakes on growth. Preterm infants are affected by significant illness usually associated with immaturity. They often become malnourished because of intercurrent morbidity or because of inappropriate management. Such infants, when fed adequately, grow at a fast rate, but usually do not fully catch up (HACK et al., 1984; GEORGIEFF, ZEMPEL and CHANG, 1989).

Advances in neonatal clinical practices have allowed for the survival of progressively smaller infants. The overall survival rate for very low birth weight (VLBW) infants (birth weight <1500 g) is 85-90%, and for those < 800 g it is close to 60% (HACK et al., 1991b). For VLBW infants the initial days or weeks of life are characterized by significant weight loss due to catabolic illness and insufficient protein-energy supply. VLBW infants constitute in most industrialized countries 1.01.5% of all births and account for a significant proportion of neonatal and infant mortality. The accepted practice of modern neonatal care allows for a 12-15% body weight loss over the initial 10 days. After parenteral and enteral nutritional support is given, they will take 15-20 days to regain birth weight. The catch-up growth observed in these infants may last 3-8 weeks. During this time they will grow at rates of 15-30 g/kg/d, which is double the normal growth rate in utero and three times that observed in the full-term newborn. Nutritional practices have had a significant impact in shortening duration of hospitalization and improving survival.

The criteria for discharge include not only attaining basic physiologic maturity but also reaching a critical weight, usually 1800-2200 g, depending on individual center practices. Thus, growth rate for VLBW infants has medical as well as economical implications. The duration of nutritional deprivation and time to recover linear and head growth has been correlated with subsequent developmental outcome (HACK et al., 1991a; The Infant Health and Development Program, 1990). It is for these reasons that the study of nutrient needs for optimal catch-up growth of these infants has been the focus of extensive research efforts over the past decades.

The results of multiple studies provide a wide range of recommended energy and protein intakes; they vary from 110-150 kcal/kg and from 2.5-4.2 g of protein/kg daily (FOMON and HEIRD, 1986). The main sources of variance in these studies are related to fecal losses and the allowance for growth. The resting metabolic rate, including post-prandial thermogenesis, in most studies is 50-60 kcal per kg. The expenditure related to minor thermal stress despite a controlled environment is 10 kcal per kg. An additional 10 kcal/kg are provided for activity, fecal losses vary from 10 to 40 kcal/kg depending on what is fed, and the allowance for synthesis and storage (growth) is 35-60 kcal/kg. Most studies have varied both the amount of calories and protein fed, and it becomes extremely difficult to evaluate the effect of P/E ratios on weight gain and catch-up growth (FOMON and HEIRD, 1986).

Another key problem in evaluating these data is establishing the goal(s) of nutritional recovery in these infants. The present goal proposed by most national and international expert committees is a logical one: VLBW and LBW infants should attain as early as possible a body weight approximating that of a normal fetus of the same conceptional age (AAP, 1985; ZIEGLER, 1986; HEIRD and KASHYAP, 1989). A second goal that is often not specified is that the quality of the tissue gain be similar to that accreted normally in utero during the equivalent gestation period (the ratio of lean to fat stored at 32 weeks is approximately 1/1). The body of available information indicates that the first goal is achievable with presently available formulations (BROOKE, ALVEAR and ARNOLD, 1979; REICHMAN et al., 1981; REICHMAN et al., 1982; CHESSEX et al., 1983; PUTET et al., 1984).

These studies also show that in most cases the fat/lean ratio of tissue gained ex utero is higher than what is normal in utero. The higher fat/lean ratio of weight gain of VLBW infants during catch-up can be interpreted as an unavoidable consequence of post-natal nutrition and growth regulation. Alternatively, it may be interpreted as resulting from inadequate nutrient supply for optimal lean tissue accretion. Heird and others have proposed that this problem results from the absolute energy supplied and the P/E ratio of the formula, while others have suggested that micronutrients may be critical to optimize lean tissue gained.

Recent experimental observations in VLBW infants indicate that it is feasible, by a gestational age of 40 weeks ex utero, not only to attain but even exceed growth rates in utero while at the same time adding sufficient lean tissue to reach a weight and body composition that are the equivalent to those of a normal baby at birth (PUTET et al., 1984; KASHYAP et al., 1986; 1987; 1988). This required not only a higher energy intake (150 kcal/kg rather than 98 kcal/d) but also that protein be increased from an intake of 3.3 g/kg to an intake of 4.5 g/kg/d. The authors conclude that a high energy intake is required to optimize protein utilization for optimal catch-up. This study is one of the few that varied energy and protein intakes independently.

The observations also show a significant correlation between the urinary excretion of C-peptide and weight gain. The high-energy, high-protein group had significantly higher C-peptide excretion, suggesting that insulin response was greater. The accretion of fat was higher than in utero, yet since the normal fetus will increase fat gain during the last weeks of gestation, it is possible that with the high-protein, high-energy diets the relative excess of fat will decrease with advancing age.

Based on metabolic balance and growth observations on over 100 infants, Heird has proposed and validated simple linear equations that relate weight gain of VLBW infants during recovery to energy intake, protein intake and birth weight; similarly, N retention can be predicted from intake, and energy stored predicted from energy intake. These equations permit the estimation of lean tissue and fat tissue gained from energy balance and N-balance data, which in turn are predicted from N and energy intake.

A prospective experimental validation of this approach to meet the goals of optimal nutrition for VLBW infants has recently been reported (HEIRD and KASHYAP, 1989). The observations demonstrated that, on high-energy (142 kcal/kg) and high-protein (4.2 g per kg) diets, full catch-up is possible, and lean tissue accretion paralleling in utero rates is feasible. The only undesirable effect, as predicted from the equations, is excessive fat storage. In attemps to improve catch-up growth of VLBW infants, a pending issue is how to enhance protein utilization without increasing energy stored as fat.

The use of high-carbohydrate, low-fat energy sources can be proposed as the next logical step based on the known effects of carbohydrates on insulin and IGF release (BRESSON et al., 1989). Another approach might be to intervene by adding factors that enhance N retention; growth hormone, IGF-I and insulin would be likely candidates (ARIZTIA et al., 1969; MONCKEBERG et al., 1963; PREVOST-THIERIOT, 1988). The use of specific amino acid blends that induce anabolic hormones might be yet a third approach to attain this goal; arginine and the branched-chain amino acids may be considered, since under catabolic conditions they may promote N retention.

The use of high-carbohydrate diets may pose special problems for infants with cardiorespiratory problems, since CHO fuel oxidation leads to higher carbon dioxide formation and may also increase energy expenditure, if the excess energy is converted to fat rather than contributing to lean tissue synthesis (KURZNER et al., 1988). This is an area that clearly needs further investigation. The results may offer new insights on how to optimize lean body mass accretion in malnourished infants and children with primary and secondary malnutrition.

The use of whole-body protein and nitrogen kinetic techniques has led to a clearer understanding of P/E relationships in the neonate as well as in other groups. Preterm infants have been preferred experimental subjects for these studies since they are small and have high turnover rates. Thus, they require less isotope dose and will attain steady state faster than older subjects. They are usually on controlled intakes, and since less is known of their true requirements it is ethically permissible to evaluate ranges of intakes that may have an impact on metabolic outcomes.

The published information indicates that the low birth weight infant has an extraordinarily high rate of protein synthesis. When 13C plasma leucine is used to assess synthesis, the reported rate is 5-10 g/kg/d, whereas using 15N glycine and urinary urea enrichment the values have ranged from 13 to 26 g of protein/kg/d (NICHOLSON et al., 1970; BIER and YOUNG, 1986; DENNE and KALHAN, 1987). The variance in these studies can be explained by clinical and experimental conditions under which the studies were conducted.

In any case, the observations indicate that both synthesis and breakdown are extraordinarily active and that only a small proportion of what is synthesized is actually stored. If 12 g are synthesized and 2 g stored then 10 g must be catabolized; thus, only about 20% of synthesis is actual storage. Protein synthesis is an energy-demanding process, and the energy cost of tissue gain in the neonate must include this cost. WATERLOW (1986) has suggested that close to half of the cost of lean body mass gain in the neonate can be explained by the energy cost of protein synthesis.

This has been validated by experimental studies demonstrating that for each 1 g of protein stored, 5 g are synthesized. This resulted in an energy cost of 10 kcal, and thus 2 kcal were required per g of protein synthesis (CATZEFLIS et al., 1985; BEAUFRERE et al., 1990). This may be considered wasteful but, on the other hand, the system, as it operates, offers multiple sites for regulation and adaptation that would otherwise not be available.

The high protein turnover rate favors tissue remodeling and appears to be a precondition for rapid growth. In the final analysis, it is the balance between synthesis and catabolism which determines protein accretion. Dietary energy, protein, and hormonal regulators affected by maturation and nutrient supply affect rates of synthesis and breakdown. Two mechanisms may account for net protein accretion in response to diet: either protein synthesis increases or protein breakdown decreases. Of course, both may also occur concomitantly.

The evidence available from leucine oxidation kinetics indicates that in the full-term infant it is the activation of synthesis after feeding which determines protein accretion, but in the premature infant, where synthetic rates are extremely high, it is the inhibition of breakdown after feeding which determines net accretion (DENNE, KARN and LIECHTY, 1991a; c). It has been suggested that, if protein synthesis is low, accretion after feeding will be mediated by increases in synthetic rates; conversely, if synthetic rates are already maximal, the inhibition of breakdown will serve to increase accretion.

A few studies in the newborn have addressed the effect of protein-energy interactions on turnover rates. The available information from these studies indicates that energy supply over 60 kcal/kg is needed to sustain protein synthesis, and that amino acid quantity, quality and route of delivery affect turnover rates (DENNE, KARN and LIECHTY, 1991b). A controlled study demonstrated that rates of synthesis and breakdown as measured by 15N glycine were not affected in premature infants receiving 60 vs 90 kcal/kg/d parenterally (DUFFY et al., 1981). Less is known on the effect of the type of non-protein energy sources on turnover rates, although the effect of fuel sources on energy balance has been verified in the neonate (DENNE, KARN and LIECHTY, 1991a). A recent report suggests that fuel source affects amino acid oxidation rates and protein breakdown but not synthetic rates. Infants given parenteral glucose and lipid had lower rates of breakdown relative to a group receiving only glucose as a source of non-protein energy (BRESSON et al., 1991).

The special case of the small-for-gestational-age (SGA) LBW infant has also been evaluated, demonstrating that synthesis and breakdown rates are lower than for appropriate-for-gestational-age (AGA) infants (CAUDERAY et al., 1987). The SGA (birth weight 1500 g; gestational age 35 wks) group demonstrated lower synthetic rates and a 20% higher protein storage per gram of protein synthesis relative to weight matched AGA (gestational age 32 wks) infants (MICHELI and SCHUTZ, 1987; MICHELI et al., 1990). This lower synthetic rate needs to be interpreted on the basis of the known decrease in synthetic rates with advancing maturation. Thus, the lower rate may be similar to that of infants of equivalent maturation. The experimental data show a close relationship between protein synthesis, protein accretion, and energy expenditure suggesting that these processes are intimately linked.