The glucose infusion rate should maintain euglycemia. Glucose intolerance, defined as inability to maintain euglycemia at glucose administration rates < 6 mg/kg/min, is a frequent problem in VLBW infants, and especially in ELBW infants. The plasma glucose concentration should be kept below 130 mg/dL. This hyperglycemia in ELBW infants may also occur in combination with nonoliguric hyperkalemia. As discussed later (Chapter 6), these co-morbidities may be prevented with the early use of TPN.

Endogenous glucose production is elevated in VLBW infants compared with term infants and adults. High glucose production rates are found in VLBW infants who received only glucose compared to those receiving glucose plus amino acids and/or lipids. Clinical experience with hyperglycemia suggests that administration of glucose alone does not always suppress glucose production in VLBW infants. It appears that persistent glucose production is the main cause of hyperglycemia and is fueled by ongoing proteolysis that is not suppressed by physiologic concentrations of insulin. In addition, abnormally low peripheral glucose utilization may also contribute to hyperglycemia. Therefore a 5% glucose concentration instead of the standard 10% concentration of glucose may have to be used in more immature ELBW infants (<750 g).

Glucose intolerance can limit delivery of energy to the infant to a fraction of the resting energy expenditure, resulting in negative energy balance. Several strategies are used to manage this early hyperglycemia in ELBW infants as well as to increase energy intake.

1. Decreasing glucose administration until hyperglycemia resolves (unless the hyperglycemia is so severe that this strategy would require infusion of a hypotonic solution).

2. […]

An in-depth nutritional assessment requires dietary, anthropometric, biochemical, and clinical data. However, the taking of anthropometric and biochemical measurements is difficult; therefore, nutritional assessment in neonates receiving intensive care treatment is frequently confined to detecting fluctuations in weight gain and in caloric intake. Nonetheless, it is necessary for the clinician to be able to assess the neonate's nutritional status because of the potentially serious sequelae of malnutrition on multiple organ systems and the importance of growth (especially brain growth) to developmental outcome. The provision of energy and nutrients at levels to support growth and development is the goal of nutrition support for VLBW infants.

Nutritional assessment includes considering the length of gestation and adequacy of intrauterine growth as well as nutrient tolerance. Static assessment (current balance between intake and output) as well as a dynamic assessment (evaluation of infant's growth over time or growth velocity) of each infant are both important. Also, the nonnutritional factors such as disease state, morbidities, and medications must be considered.

Body weight

Weight gain is the most frequently used anthropometric measure. It is important to use the same scale, obtain weight measurements at the same time each day to avoid diurnal variations, and indicate any equipment being weighed (especially arm boards and dressings); if equipment is not recorded, changes in weight may be spurious. In preterm infants, weight gain should be expressed on a gram per kilogram per day basis.

Providing optimal nutrition to a VLBW infant is difficult because there is no natural standard for comparison. For the healthy full-term infant, human milk is considered the “gold standard.” Human milk is used as the reference for the development of commercial infant formulas. While the milk of mothers who deliver their infants prematurely transiently has higher nitrogen, fatty acid content, sodium, chloride, magnesium, and iron, it is still inadequate for other nutrients, especially calcium and phosphorus. Therefore premature breast milk cannot be used as a standard for the development of premature infant formula. The special premature infant formulas use data from the accretion rates of various nutrients relative to the reference fetus, and from clinical studies of the development of the gastrointestinal tract which have defined the efficiency of absorption of nutrients and from metabolic studies.

The premature infant formulas are whey-predominant, which produces less metabolic acidosis than casein-predominant formulas in VLBW infants. The risk of lactobezoar formation is reduced when a whey-predominant formula is used. In addition, the concentration of protein per liter is approximately 50% greater than that of standard infant formula to provide three to four grams protein/kg per day (depending on volume fed). The fat is approximately 50% LCT and 50% MCT. The vitamin concentration is higher because the volume of formula consumed is significantly less in the VLBW infant. The calcium and phosphorus content is greater than standard formula, with some variation between formula manufacturers. The calcium-to-phosphorus ratio generally is 2:1 as compared to 1.4:1 to 1.5:1 with standard infant formulas.

The 24-week fetus is composed of 90% total body water (TBW). Cell membranes separate intracellular water and extracellular water spaces. Sixty-five percent of TBW is in the extracellular (ECW) compartment and 25% is intracellular (ICW). As gestation proceeds towards term, TBW decreases to 74% of total body weight and the extracellular and intracellular volumes are 40% and 35%, respectively. Potassium (K+) is the major ion of the ICW and potassium's intracellular concentration is impaired by insufficient supplies of oxygen and energy. The major ion of ECW is sodium (Na+) and the major anion is chloride (Cl−).

The preterm infant is in a state of relative extracellular fluid volume with an excess of TBW compared with the full-term infant. VLBW infants are vulnerable to imbalances between intra- and extracellular compartments. The dilute urine and negative sodium balance the first few days after birth in the preterm infant is an appropriate adaptive response to extrauterine life. Therefore, the initial diuresis is physiologic, reflecting changes in interstitial fluid volume. This diuresis should be considered in the estimation of daily fluid needs. As a result, a gradual weight loss of 10–15% in a VLBW infant during the first week of life is expected without adversely affecting urine output, urine osmolality, or clinical status. Provision of large volumes of fluid to provide increased nutrition, for example, 160 to 180 mL/kg/d, does not prevent this weight loss and appears to increase the risk of the development of patent ductus arteriosus, intraventricular hemorrhage, bronchopulmonary dysplasia (BPD), and necrotizing enterocolitis (NEC).

Introduction

The Short Bowel Syndrome (SBS) is the loss of intestinal length and absorptive surface area due to surgical resection. The loss of this mucosal absorptive surface area results in malabsorption and rapid transit potentiating malnutrition, recurrent dehydration, and electrolyte abnormalities. The most common cause of SBS in preterm infants is necrotizing enterocolitis with extensive resection. Other causes include resection following congenital malformations such as midgut volvulus from malrotation, intestinal atresias, and gastroschisis. VLBW infants with SBS require total parenteral nutrition (TPN) to provide the essential nutrients to sustain life and promote growth. The remaining bowel may be insufficient in length and function to utilize enteral nutrition. More than 80% of infants and children survive after extensive small bowel resection in the neonatal period. Prognosis is related to adjusted intestinal length, the presence of an ileocecal valve, colon preservation and occurrence of cholestasis. Most of the deaths in patients with SBS are caused by liver failure or sepsis and occur during the first year of life. The time for which the infant is dependent on TPN is significantly influenced by the length of residual intestine and the absence of an ileocecal valve. The goal in the nutritional management of these infants is to gradually advance enteral nutrient delivery while the residual bowel adapts, and simultaneously weaning and discontinuing TPN while avoiding life-threatening liver disease. Ultimately the goal is for the infant to achieve normal growth and development by consuming an oral diet.

There has been increased interest in iron deficiency, with data suggesting that mental and developmental test scores are lower in infants with iron deficiency anemia and that iron therapy sufficient to correct the anemia is insufficient to reverse the behavioral and developmental disorders in many infants. This indicates that certain ill effects are persistent depending on the timing, severity, or degree of iron-deficiency anemia during infancy.

Iron stores in the preterm infant are lower than in the term baby because these stores are relatively proportional to body weight. Iron depletion occurs at the time the infant doubles her/his birth-weight and thus iron therapy should begin by two to four weeks of life in the preterm infant when enteral feedings are tolerated. VLBW infants may need as much as 4–6 mg/kg per day, with about 2 mg/kg per day provided by iron-fortified formula and the remainder as iron supplementation at 2–4 mg/kg per day. A higher dose is also necessary for infants being given erythropoietin. Although premature infant formulas, both with and without iron fortification, are manufactured with ample amounts of vitamin E and a polyunsaturated fatty acid-to-E ratio of 6.0 or greater, premature infants on human milk and receiving supplemental iron should also be supplemented with 4 to 5 mg (6 to 8 IU) of vitamin E per day. This can be readily accomplished by use of an oral multivitamin with iron.

To avoid the risk of iron toxicity related to immature antioxidant systems in VLBW infants, the AAP and other organizations do not recommend using iron prior to two weeks of age.

There are two methods used for estimating the protein intake for ELBW infants necessary to maintain the intrauterine rate of protein accretion:

1. Factorial method, which includes an estimate of inevitable urinary nitrogen losses (i.e., the losses that occur in the absence of nitrogen intake) and an estimate of the amount deposited in utero corrected for efficiency of absorption and deposition.

2. Actual intake method, which determines the actual intake that supports intrauterine rates of growth and nitrogen accretion.

Interestingly, the two approaches do not result in the same estimate of protein requirement. The factorial method, depending on the assumptions made concerning inevitable nitrogen losses and efficiency of absorption and deposition, usually yields an estimate of approximately 4 g/kg per day to support intrauterine rates of growth and protein accretion. The actual intake method suggests that a protein intake of approximately 3 g/kg per day supports intrauterine rates of growth and nitrogen accretion.

Replicating the body composition of the fetus of the same postconceptional age as the preterm infant is as important a goal as achieving the fetal rate of weight gain. This strategy of promoting accretion of more lean mass but less fat deposition may have life-long implications. It appears with current strategies we may be promoting fat deposition and not enough lean mass. However, insufficient data are available concerning the body composition of infants fed different nutrition regimens.

Although breast milk is considered the ideal food for the term infant, for the VLBW infant it provides inadequate amounts of several nutrients, especially protein, vitamin D, calcium, phosphorus, and sodium. While large volumes of human milk (180 mL/kg/d) provide the energy sufficient to enable nearly all infants with birthweights <1250 g to gain weight at intrauterine rates (approximately 15 g/kg/d), the protein content is suboptimal, and may result in lower serum albumin and transthyretin (prealbumin) levels, which are reliable indicators of protein nutrition in preterm infants. The calcium and phosphorus content is low in unsupplemented human milk regardless of large volumes in comparison with that required to achieve intrauterine accretion rates, resulting in poor bone mineralization in VLBW infants. In addition, the sodium content of human milk results in less sodium retention than intrauterine estimates and may result in hyponatremia and may be rate-limiting for appropriate weight gain

Lucas and colleagues (1984) found that infants weighing less than 1200 g at birth fed unfortified human milk were less than two standard deviations below the mean for weight for age when they reached 2.0 kg. Therefore, infants weighing less than 1.0 kg at birth who were fed unfortified human milk would be expected to take three weeks longer to reach a weight of 2.0 kg than infants receiving preterm formulas.

In a study focusing on developmental outcomes, Lucas et al. (1989) observed that infants receiving breast milk had a significantly higher intelligence quotient at eight years than formula-fed infants. These studies included infants receiving unfortified donor human milk.

Protein hydrolysate formulas are designed for infants who are allergic to cow's milk or soy proteins. Some protein hydrolysate formulas are also elemental with the carbohydrate in easily absorbable forms, such as glucose polymers or monosaccharides, and the fat as both medium-chain and long-chain triglycerides. These are sometimes used in the management of infants with intestinal resection or intractable diarrhea. These formulas can be loosely categorized according to the extent that the protein is hydrolyzed: (1) 100% free amino acid-containing formula (SHS Neocate); (2) extensively hydrolyzed protein-containing formula (Enfamil Nutramigen, Enfamil Pregestimil, Similac Alimentum); and (3) partially hydrolyzed protein-containing formula (Carnation Good Start) (Table 19.1).

All of these protein hydrolysate formulas provide 67–68 kcal/dL energy. These formulas are not routinely recommended for VLBW infants but are used frequently in VLBW infants after intestinal resection resulting from NEC. A recent review by Szajewska concluded there was little evidence to support the use of extensive and partial protein hydrolysate formulas for preterm infants.

The use of intravenous lipids is essential to a complete TPN regimen. Lipids serve as a source of linoleic acid to prevent or treat essential fatty acid deficiency (EFAD), and as an energy source. Larger quantities serve as a partial replacement for glucose as a major source of calories (balanced TPN).

The VLBW infant is especially susceptible to the development of EFAD because tissue stores of linoleic acid are small and requirements for essential fatty acids are large secondary to rapid growth. The human fetus depends entirely on placental transfer of essential fatty acids. A VLBW infant with limited nonprotein energy reserve must mobilize fatty acids for energy when receiving intravenous nutrition devoid of lipid. Our own studies in these infants confirm other studies that show that biochemical evidence of EFAD can develop in the VLBW infant during the first week of life on lipid-free regimens.

Standard 20% emulsions contain a lower phospholipids emulsifier/triglycerides ratio than standard 10% lipid emulsions and should preferably be used for TPN. Clearance of lipid emulsions from the blood depends on the activity of lipoprotein lipase. Post-heparin lipoprotein lipase activity can be increased by relatively high doses of heparin; heparin does not improve utilization of intravenous lipids. Therefore the increase in lipase activity by heparin lends to an increase in FFAs which may exceed the infants ability to clear the products of lipolysis. The premature infant can clear 0.15 to 0.2 g/kg/hr of lipids.

“NECiphobia” (the fear of NEC) is the most prevalent reason clinicians withhold enteral feedings in VLBW infants. NEC most frequently occurs in VLBW infants who have received enteral nutrition. When parenteral nutrition is used exclusively for the provision of nutrients, the absence of enteral feedings is associated with morphologic and functional changes in the gut with a significant decrease in intestinal mass, a decrease in mucosal enzyme activity, and an increase in gut permeability. The changes are due primarily to the lack of luminal nutrients rather than the TPN. Therefore, parenteral nutrition does little to support the function of the gastrointestinal tract. The timing of the initial feedings for the preterm infant remains controversial. As pediatric TPN solutions designed for neonates became available, many clinicians chose to use parenteral nutrition exclusively in the sick, ventilated, preterm infant because of concerns about necrotizing enterocolitis. Total parenteral nutrition was thought to be a logical continuation of the transplacental nutrition the infants received in utero. However, this view discounts any role that swallowed amniotic fluid may play in nutrition and in the development of the gastrointestinal tract. In fact, by the end of the third trimester, the amniotic fluid provides the fetus with the same enteral volume intake and approximately 25% of the enteral protein intake as that of a term, breastfed infant. Studies in animals maintained in an anabolic state with TPN, but deprived of enteral substrate, confirmed that intraluminal nutrition was necessary for the development of normal gastrointestinal structure and functional integrity. Enteral feedings have both direct trophic effects and indirect effects secondary to the release of intestinal hormones.

Introduction

Neonatal cholestasis is frequently encountered in infants hospitalized for prematurity, gastrointestinal malformations (such as gastroschisis, omphalocele, short gut syndrome, biliary atresia, Alagille syndrome), infection, hemolytic disorders, endocrinopathies (such as hypothyroidism and hypopituitarism), and metabolic abnormalities (such as alpha-1-antitrypsin deficiency, galactosemia). It is common among preterm infants because of immature hepatobiliary function, associated infections, and exposure to hepatotoxic agents such as parenteral alimentation fluids (TPN). Cholestasis is defined as conjugated hyperbilirubinemia (serum conjugated bilirubin concentration greater than 2 mg/dL) because of diminished bile flow and/or excretion of conjugated bilirubin from the hepatocytes into the duodenum. The conjugated fraction of serum bilirubin is normally no greater than 15% of the total serum bilirubin concentration. The incidence of neonatal cholestasis is approximately 1:2500 live births. Once cholestatic liver disease is identified, prompt diagnosis and treatment are necessary.

Cholestasis is a common complication of long-term parenteral nutrition, especially in VLBW infants. If TPN is administered long-term, management should be focused on preventing occurrence of parenteral nutrition-associated cholestasis (PNAC). In this chapter, causes and strategies for reversal and/or prevention of total parenteral nutritionassociated cholestasis (TPNAC) will be discussed.

Potential causes of TPNAC

TPNAC is the leading cause of neonatal cholestasis and the primary indication for combined liver and intestinal transplantation in children. Within 2 weeks of TPN, biochemical changes in several liver enzymes indicative of hepatic dysfunction appear. Serial measurement of the serum concentration of conjugated bilirubin is necessary to monitor the progression of cholestasis.

The amount of enteral calcium, phosphorus, and magnesium intake required to match intrauterine accretion rates is high: calcium 185 to 200 mg/kg per day, phosphorus 100 to 113 mg/kg per day, and magnesium 5.3 to 6.1 mg/kg per day. VLBW infants with a less complicated clinical course may require lower intakes. The American Academy of Pediatrics recommends intakes of calcium of 185 to 210 mg/kg per day, phosphorus 123 to 140 mg/kg per day, and magnesium 8.5 to 10.0 mg/kg per day. However, magnesium intake at this level with such high calcium and phosphorus intake results in negative magnesium balance; therefore, a higher intake of magnesium approximately 20 mg/kg per day may be needed.

The recommendation for vitamin D, which is required for normal metabolism of calcium, phosphorus, and magnesium, has ranged from 200 to 2000 IU per day for the preterm infant. VLBW infants can maintain normal vitamin D status with 400 IU per day. Providing high-dose vitamin D supplementation does not decrease the incidence of osteopenia in VLBW infants.

Human milk has concentrations of calcium and phosphorus that are appropriate for full-term infants. These amounts are inadequate for the VLBW infant. Breast milk should be supplemented with additional calcium, phosphorus, and vitamin D, which can easily be done with a powdered human milk fortifier (Enfamil Human Milk Fortifier, Mead Johnson, Evansville, IN; Similac Human Milk Fortifier, Abbott Laboratories, Columbus, OH). Also recently available is a human milk fortifier (Prolact + H2MF, Prolacta, Bioscience, Monrovia, CA).

Recommendations for mineral and vitamin D intake for preterm infants are based on metabolic studies with the goal being optimizing bone and mineral homeostasis associated with normal serum minerals and vitamin D metabolites and, most important for the VLBW infant, normal bone density.

The molar Ca:P ratio is 1.3 in the whole body and 1.67 in the bone mineral apatite. Ninety-seven percent of whole body calcium and 80% of whole body phosphorus are stored in the apatite together.

Serum calcium exists in three fractions: ionized calcium (∼50%), protein-bound calcium (∼40%), and a small amount of calcium that is complexed, primarily to citrate and phosphate ions. Serum calcium is maintained at a constant level by the actions of principally parathyroid hormone and calcitonin.

In the presence of low phosphate intake the kidney retains phosphate and it disappears from the urine. Hypercalcemia and hypercalciuria may result from phosphate deficiency. Deficiency of phosphate results in bone demineralization and osteopenia of prematurity. Calcium is actively transported across the placenta in the third trimester of gestation; thus an infant born in the third trimester, especially early in that trimester, is born relatively osteopenic and strategies to maintain calcium homeostasis are of paramount importance.

TPN for VLBW infants typically provides minerals to meet about 60–70% of intrauterine mineral requirements. Early TPN when reaching volumes of 120–130 mL/kg/d contains calcium at 60–90 mg/kg/d, phosphorus at 47–70 mg/kg/d, magnesium at 4.3–7.2 mg/kg/d and vitamin D at 40–160 IU/kg/d (Table 7.1). VLBW infants on TPN for longer duration (> two weeks) should receive an approximate 33% increase in calcium and phosphorus concentration in their infusate.