Nutritional Requirements
and Strategies
9
Nutritional Requirements of the Very-Low-Birthweight Infant
Patti J. Thureen, MD and William W. Hay, Jr., MD
d Differences between Fetal and Neonatal Nutrition
d Current Understanding of Specific Nutrient Requirements of the Very Preterm Infant
d Evidence-Based Approaches for Providing Parenteral and Enteral Nourishment to Low-Birthweight Infants
d Summary and Future Challenges
Advances in perinatal care of neonates between 24 and 30 weeks of gestation and 500 and 1500 grams birthweight have markedly improved the survival rates of these very small and very preterm infants. After birth, nutrition to support the growth and development of these infants must now be provided by intravenous (IV) and enteral routes rather than by the placenta. Very-low-birthweight (VLBW, defined as <1500 g in weight), very preterm infants have unique nutritional and metabolic substrate requirements for energy balance and growth, predicted by a high protein turnover rate, high metabolic rate, and high glucose utilization rate.
Extrauterine stresses add to these nutritional requirements of the fetus of compa- rable gestational age. The VLBW very preterm infant has endogenous energy reserves of only about 200–400 kcal, enough to maintain energy balance for only about 3 or 4 days without an exogenous energy supply. Thus the VLBW infant is extremely vulnerable to inadequate nutritional intake. Growth and development of sensitive organs, particularly the brain, clearly are dependent on unique, though variable, mixes of specific nutrients, provided at optimal rates and by safe and efficacious routes. There also is abundant evidence from animal experiments and human observational studies that prolonged undernutrition during critical periods of devel- opment (between 22 and 40 weeks postconceptional age for humans) adversely affects long-term growth and neurodevelopmental and cognitive outcomes. Nutri- tional strategies for very preterm infants generally do not provide sufficient protein to meet normal fetal requirements for growth and universally are producing post- natal growth failure from which such very preterm infants do not recover by hospital discharge at term gestation.1-3 Such undernutrition of protein has been overcompensated by high rates of carbohydrate and lipid intakes, producing fatter infants at term than would have been the case had they remained in utero and growing at normal rates.4 Nutritional practices in preterm infants vary consider- ably, and there are no definitive regimens that have been shown to safely provide nutrition while optimizing growth and development of these infants. Despite the advances in nutrition of these infants, therefore, we now are at a new threshold of determining which nutrients we should provide to these infants, as well as the best rates, mixtures, and means needed to optimize their growth and develop- ment.5 There is reason to do this: studies are consistently demonstrating that improved neurodevelopment when such very small, very preterm infants are fed more protein and energy earlier after birth than has been common practice in many institutions.6
107
B
Differences between Fetal and Neonatal Nutrition
The currently recommended standard for providing comprehensive postnatal nutri- tion to very preterm infants is one that meets the unique nutritional requirements of the growing human fetus and replicates normal in utero human fetal growth and development.7 To date, however, this long-standing recommendation by the Ameri- can Academy of Pediatrics has not included guidelines, let alone a rational base of evidence, about how this standard should be achieved. There remain no data in the literature to support or refute this recommendation. Therefore appreciating the dif- ferences between normal fetal nutrition and commonly used postnatal nutritional practices in very preterm neonates may be a useful first step toward developing nutri- tional strategies to meet this standard for postnatal growth in preterm neonates.
Protein
Amino acid uptake by the fetus exceeds that needed to meet requirements for net protein accretion; the excess amino acids are oxidized, contributing significantly to fetal energy production.8-10 In contrast, amino acids usually are infused into the preterm neonate in the first several weeks of life at low rates that are significantly less than those required to provide for normal rates of fetal protein accretion.
Carbohydrate
Glucose delivery to the fetus is determined by the maternal glucose concentration and occurs at rates that reflect fetal glucose utilization for energy production.11 Fetal glucose utilization rates also occur at relatively low plasma insulin concentrations that only reach neonatal levels toward the end of the third trimester of gestation.12 In contrast, glucose usually is infused into the preterm newborn at higher rates than the fetus receives in utero, frequently contributing to neonatal hyperglycemia and plasma insulin concentrations that are significantly higher than those seen in the fetus; such higher insulin concentrations can be the result of normal glucose- stimulated insulin secretion or reflect insulin resistance.13-16
Fat
At 50% to 60% of gestation, there is little fetal lipid uptake,17 indicating that energy metabolism is not dependent on fat early in the third trimester. Instead, fetal fat accumulation only gradually increases toward term.18 At this early stage of develop- ment, fetal lipid uptake involves primarily the essential fatty acids, which are neces- sary for membrane development, particularly in cells of the central nervous system and in red blood cells. During the latter part of the third trimester, fetal lipid uptake and deposition in adipose tissue increase markedly, producing a term fetus with 12%
to 18% body weight as fat.8,18 In contrast, in the very preterm newborn infant, lipid is commonly provided as an energy source in amounts that exceed in utero delivery rates, contributing to adipose tissue production much earlier in development and in excess of rates that occur gradually over the third trimester of fetal development.4 Accelerated lipid infusion and oxidant injury from metabolic products of IV lipid infusates also contribute to cholestasis.19
Consequences of a Non-Fetal Diet in Preterm Infants
Clearly, current nutritional practices in preterm infants (high energy intakes of lipid and glucose accompanied by low protein intakes) contrast with the nutrient supplies that the normally growing fetus receives (high amino acid uptake with just sufficient uptakes of glucose and lipid) (Table 9-1). The risks and benefits of these contrasting nutritional patterns for the growth and development of the VLBW very preterm infant are not completely known. There is mounting evidence and thus concern, however, that the high-energy, low-protein diet currently provided to very preterm infants, producing both growth restriction and a higher body composition ratio of fat to lean body mass,4 can produce a predilection to later life obesity, insulin resis- tance, and type 2 diabetes, similar to the long-term outcomes of the intrauterine growth restriction (IUGR) in fetuses of the same gesta tional age.20,21
9
Table 9-1 FETAL VERSUS PRETERM NEONATAL NUTRITION Normal Fetal Nutrition
Amino acids are actively transported by the placenta into the fetus at rates greater than the fetus uses for net protein accretion.
The excess amino acid supply is oxidized for energy.
Glucose and lipids are taken up and used by the fetus at rates that meet energy needs.
Contrasting “Customary” Very-Low-Birthweight Nutrition
Glucose is infused intravenously into the infant at rates higher than the infant uses for oxidative metabolism.
The excess glucose infusion produces hyperglycemia.
Amino acids are infused at rates less than needed for normal rates of protein accretion and growth.
Table 9-2 GENERAL PRINCIPLES OF EARLY POSTNATAL NUTRIENT REQUIREMENTS OF THE VERY PRETERM INFANT
Metabolic and nutritional requirements do not stop with birth and, in the preterm newborn, are equal to or greater than those of the fetus.
Intravenous feeding is always indicated when normal metabolic and nutritional needs are not met by normal enteral feeding, within hours, not days, of birth.
Glucose: 5-7 mg/min/kg beginning at birth, increasing to 10 to 11 mg/min/kg (38-42 kcal/kg/day) for full intravenous nutrition; adjust frequently to keep plasma glucose concentration >60 and <120 mg/dL.
Lipid: to meet additional energy (and EFA) needs; 2-3 g/kg/day = 18-27 kcal/kg/day Amino acids: Infuse at rates just higher than the infant can use, but at rates appropriate
for the developmental stage of protein turnover and growth: 3-4 g/kg/day at 23-30 weeks gestational age, 2.5-3 g/kg/day at 30-36 weeks gestational age, 2-3 g/kg/day at 36-40 weeks gestational age.
Oxygen: Remember that blood oxygen content (percent saturation times hemoglobin concentration) directly affects growth, regardless of the PaO2.
Minimal enteral feeding (MEF), also called “priming,” “trophic,” or “non-nutritive”
feeding: Generally breast milk and/or formula at intakes of 5 to 25 mL/kg/day are safe to start on postnatal day 1 in stable preterm infants, even as early as 24 weeks’
gestation, do not increase the risk for necrotizing enterocolitis, and do promote gut growth and development in contrast to intravenous nutrition.
Improved understanding of specific nutrient requirements at early gestational ages is required, therefore, to develop optimal parenteral and enteral nutritional strategies for extremely preterm neonates, not only to produce normal growth and development but also to prevent later life disorders that contribute to major adult morbidity and mortality.
Current Understanding of Specific Nutrient Requirements of the Very Preterm Infant
Current knowledge of the nutritional requirements of preterm infants has been extrapolated from both animal and human fetal research as well as the growing body of literature from neonatal studies (Table 9-2).
Glucose
The very preterm infant has high energy requirements produced by the relatively large body proportions of very metabolically active organs (primarily the brain, but also the heart, liver, and kidney) at this early stage of development.8,22 Thus the very preterm infant requires a large and continuous supply of glucose for energy metabo- lism. Because glycogen content is relatively limited in the very preterm infant, unless glucose is supplied directly, glucose deficiency and hypoglycemia commonly develop in these infants.
The minimal fetal glucose requirement has been measured directly in fetal sheep and is approximately 9 mg/kg per minute between midgestation and the
B
start of the third trimester.23 By term gestation, the fetal glucose requirement falls to about half this rate. Similar rates of glucose utilization have been estimated from endogenous glucose production rates in stable very preterm infants with sufficient glycogen stores and in term infants.24-27 These rates of glucose supply represent the minimal rates necessary to maintain adequate energy supply to the brain because glucose is the principal energy substrate of the fetal brain. Glucose intake needed to support the energy costs of protein synthesis and deposition adds an additional requirement of about 2 to 3 mg/kg per minute. Thus very preterm neonates usually require about 9 to 10 mg/kg per minute of glucose to meet all of their glucose utilization needs.28 This total supply is variably provided by endogenous glucose production and IV infusion. A common and usually successful initial rate for IV glucose infusion in the very preterm infant is about 5 to 7 mg/kg per minute, which allows for the variable rates of endogenous glucose production to provide for addi- tional glucose needs. By term gestation, total glucose requirements and initial IV infusion rates decline to 5 to 6 and 3 to 4 mg/kg per minute, respectively. This decline occurs because bone, muscle, and fat, which do not use glucose at the higher rates of the brain and heart, contribute more to body composition and thus dilute the body-specific rates of glucose utilization seen at earlier gestation.
Minimal Glucose Requirements
From a clinical standpoint, the minimal glucose requirement is that which maintains an “acceptable” range of glucose concentrations. Definition of this range of accept- able glucose concentrations varies considerably among clinicians and lacks experi- mental verification. If it is assumed that the fetal glucose concentration is the appropriate reference for preterm infants of the same gestational age, then a reason- able normoglycemic range for the preterm infant can be obtained by measuring the plasma glucose concentration in the fetus at similar gestational ages. Several studies have reported normal fetal glucose concentrations in umbilical venous blood obtained at the time of cordocentesis.29,30 From these data, it can be extrapolated that the lower limit of normal glucose concentration over the gestational age range of 24 to 32 weeks is about 3 mM (about 54 mg/dL), which is considerably higher than current definitions of neonatal hypoglycemia. Whether such relatively higher glucose concentrations should be maintained in preterm infants has not been tested and remains controversial, particularly when such infants are asymptomatic. For example, one retrospective study indicated that neurodevelopment was progressively impaired in asymptomatic preterm infants with an increasing number of days in which they had recurrent low glucose concentrations (<2.6 mmol/L [47 mg/dL]),31 yet a more recent prospective study showed that similarly asymptomatic but “hypo- glycemic” preterm infants of comparable gestational age and medical condition had no differences compared with normoglycemic preterm control infants.32
Adaptations to Low Glucose
Fetuses that develop IUGR from placental insufficiency, reduced glucose supply, and lower plasma glucose and insulin concentrations develop a “thrifty” phenotype,33 characterized by increases or at least maintenance of normal levels of cell membrane glucose transporters, both Glut-1 (the ubiquitous glucose transporter found on all cell membranes) and Glut-4 (the insulin-sensitive glucose transporter found in muscle, fat, and heart), among a variety of tissues including liver, heart, skeletal muscle, and brain.34 This upregulation (or at least maintenance of normal levels) of glucose transport capacity also is associated with increases in insulin receptor expres- sion and activity and other proteins in the insulin signal transduction pathway in cells that contribute to both glucose and insulin sensitivity. These changes combine to support the capacity for insulin and glucose in the plasma to promote normal rates of glucose uptake and metabolism despite prevailing low glucose and insulin concentra- tions in the plasma. It remains uncertain whether the insufficient nutrition of preterm infants that produces postnatal IUGR also produces a similar upregulation of glucose uptake capacity, insulin sensitivity, and glucose metabolism, but to the extent this does occur, it would contribute to excess glucose deposition in tissues such as glyco- gen and fat as well as higher than normal rates of CO2 and lactic acid production.
9 Hyperglycemia
The upper limit of the normal glucose concentration range has not been defined in preterm infants, although many references use the value of 120 mg/dL (6.7 mmol/L).35 Common clinical practice includes tolerating glucose concentrations of up to 150 to 200 mg/dL,36 which occur frequently over the first 1 to 2 weeks of life,37,38 but the safety and consequences of this practice are unknown. In the first few days of life in extremely preterm neonates, hyperglycemia likely results from endogenous glucose production in response to stress-reactive hormones, especially the catecholamines, epinephrine and norepinephrine, and glucagon.16 Catecholamines inhibit insulin secretion and diminish insulin’s action to promote glucose utilization in peripheral tissues. Along with glucagon and cortisol, they also increase rates of glycogen break- down and the release of amino acids into the circulation that then are available for increased rates of gluconeogenesis. Glucagon and cortisol activate the regulatory enzymes in the gluconeogenic pathway, and cortisol specifically promotes glucose release from the liver. After the first week of life and with improvement in physiologic condition, hyperglycemia in preterm infants more likely is due to excessive glucose infusions rates.39 Less commonly, it also could be a harbinger of infection or other disease processes associated with a systemic inflammatory response.13
Excess Glucose Infusions
Experimental evidence also documents adverse effects of persistently high glucose concentrations. In the normal ovine fetus, persistently high glucose concentrations from direct glucose infusion lead to reduced Glut-1 and Glut-4 transporters in a variety of tissues and the development of insulin resistance and glucose intoler- ance.34,40 The same complications have been observed in neonatal piglets treated with total parenteral nutrition (TPN), but without such high or persistent glucose concentrations, indicating that just continued IV glucose supply in excess of normal rates could contribute to mechanisms in peripheral cells that suppress glucose toler- ance and insulin sensitivity.14 With even higher and persistent glucose concentrations from direct IV glucose infusion, fetal sheep also gradually develop a suppression of insulin production or secretion in response to glucose stimulation, even to the point of suppressed basal insulin concentrations. These potential reductions in glucose and insulin sensitivity might compete with those noted previously involving upregulated glucose and insulin sensitivity in IUGR infants. The results of such competition of metabolic responses to hyperglycemia and IV glucose infusion present a compelling and urgent need for research to define the presence or absence of these conditions in preterm infants treated with prolonged and high rates of glucose infusion as part of TPN regimens. Such research also should address the ill-defined but relatively common practice of tolerating higher than normal glucose concentrations (see later), how and when they develop, how to monitor their responses to treatments, and their potential contributions to short-term morbidity and longer-term consequences of obesity, insulin resistance, and glucose intolerance. Such research is urgently needed as independent studies in surgical and medical intensive care units continue to docu- ment serious morbidity during prolonged periods of hyperglycemia, including decreased immunity, increased rates of infection, poor wound healing, and loss of skeletal and cardiac muscle. Although evidence is mixed, there is some indication that tight glucose control, even involving insulin infusions, reduces these adverse effects of prolonged hyperglycemia in adults in intensive care units.41,42 Similar studies should be done in neonates to determine whether such morbidity also occurs in the neonatal intensive care unit (NICU) and whether insulin therapy is necessary beyond reduction in IV glucose infusion rates to reduce such morbidity.
The upper limit for the rate of IV glucose administration is that above which glucose supply exceeds the energy needs of the body, the metabolic capacity for glucose oxidation, and the production of glycogen. Under these conditions the excess glucose infused and taken up by cells is converted to fat. Glucose conversion to fat is an energy-inefficient process that results in increased energy expenditure, increased oxygen consumption, and increased carbon dioxide production. The latter has the potential to produce CO2 retention that may exacerbate existing lung disease,
B
particularly in infants with chronic lung disease of prematurity or bronchopulmo- nary dysplasia.43 High glucose infusion rates in fetal sheep, for hours as well as days, contributes to reduced PaO2 and blood oxygen content values and the development of lactate production and metabolic acidosis.44 Whether this occurs in preterm infants is not known, but it could be an adverse aspect of attempts to maximally infuse glucose during TPN. The rate of glucose administration that exceeds the maximal glucose oxidative capacity is not completely known in neonates but prob- ably is more than 11 to 13 mg/kg per minute (about 18 g/kg per day); this value may be lower if lipid also is given.26,45 High rates of glucose infusion also contribute to fatty infiltration of the liver and heart with potentially serious consequences, including the potential for impaired efficiency of ventricular oxygen utilization, contractile function, and stroke work during heart failure.46-48
Fat
The most remarkable aspect of lipid development during late fetal life in humans is the deposition of large amounts of body fat, up to12% to 18% of body weight.18 The biological value of this adiposity is not clear, nor are the mechanisms that produce it. Whether this developmental growth pattern of high fat deposition during the last third of pregnancy should be recapitulated in preterm infants of the same gestational age is not known. Because such infants are currently fed diets high in carbohydrate and lipids, however, they usually meet or exceed normal rates of intrauterine fat deposition in adipose tissue.
Although fatty acids are not readily oxidized in the fetus, fat oxidation does develop after birth, even in very preterm infants.49 Failure to provide sufficient non- protein energy will lead to increased rates of lipolysis and oxidation of endogenously released fatty acids. This problem applies particularly to potentially excessive oxida- tion of essential fatty acids because these very preterm infants have very little adipose tissue and thus a ready supply of nonessential fatty acids. This could lead to deleteri- ous alterations in the amount and structure of critical membranes of cells of the developing central nervous system and potentially to abnormal neurologic outcome.
The roles of, requirements for, and appropriate balance of the ω-3 and the ω-6 essen- tial polyunsaturated fatty acids remain to be determined, although there is increasing evidence that increased supply of ω-3 end products, particular docosahexaenoic acid (DHA), has beneficial effects on selected aspects of development.50,51
In terms of minimal lipid intake in the VLBW infant in the early neonatal period, IV lipid is primarily administered to prevent essential fatty acid (EFA) defi- ciency and, if tolerated, to serve as an energy substrate. Unfortunately, metabolism of lipids infused intravenously may be impeded in this population by both an immaturity of mechanisms of triglyceride and fatty acid metabolism and by clinical conditions, such as infection, surgical stress, and malnutrition, that, through exces- sive catecholamine secretion and reduced insulin secretion and concentration, inhibit lipid clearance from the circulation.52 Thus, despite recognized needs for lipids for both membrane structural development and energy expenditure, hyperli- pemia is a common complication of lipid emulsion infusions, particularly when given as part of IV nutrition in the more stressed and unstable preterm infants. Lipid infusions also contribute to the development of hyperglycemia, a common complica- tion of high dextrose infusions.27 In these cases, excessive fatty acid supply augments hyperglycemia by at least two major metabolic processes. Fatty acids act com- petitively with glucose by providing carbon that substitutes for glucose carbon oxidation,49 and the oxidation of fatty acids in the liver produces cofactors that promote gluconeogenesis. Fatty acids also inhibit insulin action in the liver, thereby releasing the normal suppression of hepatic glucose production provided by insulin.53
Clinical practices vary widely regarding the upper limit of fat intake early in the neonatal course, because of unresolved controversies surrounding adverse effects of IV lipid administration. For example, older studies indicated that high rates of lipid infusion, usually at least twice the maximal rates provided to preterm infants, could possibly contribute to pulmonary vascular resistance and pulmonary artery hypertension, as well as impaired bilirubin metabolism.54,55 Later in the neonatal