Parenteral nutrition in premature infants

INTRODUCTION — Parenteral nutrition (PN) was first used in newborn infants almost 50 years ago [1]. Since then, it has proven to be a valuable, life-saving tool in preterm infants who are unable to tolerate sufficient enteral feeds to meet their nutritional needs. However, the limitations and toxicities of PN have become increasingly recognized. As a result, the practice of PN continues to evolve as new products and technologies become available.

The composition, prescription, and administration of PN to premature infants will be discussed here. The composition of and transition to enteral feedings is discussed separately. (See "Approach to enteral nutrition in the premature infant".)

INDICATIONS — For most preterm infants, PN should be considered as a short-term bridge to provide nutritional support until full enteral nutrition can be provided [2]. Such instances include:

●Immediately after birth – To provide essential nutrition as enteral feeds are commenced and advanced

●During periods of acute gastrointestinal malfunction (eg, due to septic ileus or necrotizing enterocolitis)

●When infants are felt to be "too sick" to receive enteral feeds (eg, during treatment with high-dose pressors or extracorporeal membrane oxygenation)

In a small subset of infants, prolonged periods of PN may be required. These infants typically have congenital or acquired gastrointestinal malformations, including short bowel syndrome. The risks associated with PN increase with the dose and duration of PN, so the goal of care should always be to move to full enteral nutrition as quickly as possible. (See "Management of short bowel syndrome in children" and "Intestinal failure-associated liver disease in infants".)

PARENTERAL NUTRITIONAL REQUIREMENTS

Phases of parenteral nutrition

●Early PN – This phase of PN is intended to be started as soon as possible after the infant's birth, usually within a few hours after delivery [2]. Its primary goal is to prevent excessive catabolism by providing energy and protein. Secondary goals include prevention of hypocalcemia. In this phase, PN usually contains only dextrose, amino acids and calcium, but not sodium, potassium, magnesium, or phosphorus (table 1). Intravenous lipids can be included in the initial prescription, or added on the first or second day of life.

●Full PN – This phase of PN is intended to meet the entire nutritional needs of the infant and support normal rates of growth. To do so, it must contain a wide range of essential nutrients (table 1), and sufficient protein and energy to support growth.

The transition from early to full PN should be accomplished as quickly as is tolerated. Ideally, the transition occurs within three days of birth, although this may not be possible if the infant does not tolerate the glucose or lipid infusion rates required to achieve the nutrient targets. Although energy intakes of 30 to 40 kcal/kg/day and protein intakes of 1 to 1.5 g/kg/day are probably sufficient to limit catabolism early in postnatal life, much higher energy intakes are needed to achieve near-normal rates of growth. Traditionally, protein and lipid intakes were slowly increased over the first few days of life, but there is evidence that slow advancement is not necessary in most cases. (See 'Energy requirements' below and 'Amino acids' below.)

Energy requirements — Early PN should contain 35 to 45 kcal/kg/day of nonprotein energy (or 45 to 60 kcal/kg/day of total energy) (table 1). Subsequently, the energy intake should be increased as quickly as possible. In practice, this may be difficult in extremely preterm infants, who may not tolerate high intakes of carbohydrate or lipid.

Full PN should contain >65 kcal/kg/day of nonprotein energy (or 80 to 90 kcal/kg/day of total energy) to allow normal growth rates [3]. This target for energy in PN is approximately 20 percent less than required for enterally fed infants. This is because enteral feeds are incompletely absorbed, and the processes of gastrointestinal digestion and absorption impose energy costs that are not present when nutrients are provided parenterally.

Macronutrient balance — Energy in PN can be provided as carbohydrates (as glucose), lipids, and protein (as amino acids). Each of these components is necessary to achieve growth.

●Glucose – To avoid hypoglycemia and to meet the obligatory glucose needs of the developing brain, glucose should be provided at a minimum rate of 5 to 8 mg/kg/minute, starting immediately after birth (eg, 10% dextrose solution at 100 mL/kg/day). As PN is advanced, the glucose component is typically increased to around 12 to 15 mg/kg/minute, but the target rate may vary depending on the proportion of energy needs provided by lipids.

●Lipids – Lipids should provide approximately 30 to 50 percent of nonprotein energy (similar to human milk), which may help to optimize protein accretion while limiting the potential toxicity of excessive lipids. As an example, in one study, PN containing either 29 or 40 percent of nonprotein energy as fat (equivalent to approximately 2 to 3 g/kg/day of lipid) resulted in improved protein retention compared with PN with a lower proportion of fat [4]. Similarly, in a separate study, PN containing 50 percent of nonprotein energy as lipid resulted in lower protein oxidation and protein turnover, compared with a lipid-free PN with similar energy and nitrogen content [5]. In theory, PN with a higher ratio of lipid might also improve oxygenation because it has a lower respiratory quotient (the ratio of carbon dioxide [CO₂] produced: oxygen consumed). However, clinical studies have failed to substantiate this benefit. As an example, in one study that examined the effects of isoenergetic PN solutions differing in the relative amounts of fat and carbohydrate, the oxygen consumption did not vary with the macronutrient composition [6]. Although CO₂ production was higher in PN with a lower proportion of fat, there were no differences in partial pressure of carbon dioxide (PCO₂), and partial pressure of oxygen (PO₂) was higher. A possible explanation is that the higher lipid infusions adversely affected alveolar function.

●Protein – If sufficient energy cannot be provided due to lipid or glucose intolerance in the very low birth weight (VLBW) infant, providing the "target" intake of amino acid/protein will not achieve normal growth; rather, it will impose a metabolic burden on the infant as amino acids need to be catabolized. For this reason, protein requirements and nonprotein energy requirements are not independent but interlinked.

Amino acids — We suggest starting amino acids as soon as possible after birth (ie, within a few hours of birth). Early initiation of PN including amino acids for preterm infants is associated with improved short-term growth outcomes (such as the time to regain birth weight) and medium-term growth outcomes (such as discharge weight or length below the 10^th percentile for age) compared with later initiation of PN [7]. Amino acid intakes as low as 1.0 to 1.5 g/kg/day appear sufficient to prevent overt catabolism, which is associated negative nitrogen balance [8] and risk of hyperkalemia [9]. Higher intakes are required to support growth that approximates in utero accretion rates.

Our suggested target depends on the infant's weight:

●VLBW infants – For VLBW infants (birth weight 1000 to 1500 g), amino acids are usually started at 1.5 to 2.5 g/kg/day and then advanced rapidly to reach a target of 3.5 g/kg/day by the second or third day of life (table 1) [2,3]. These intakes of amino acids are associated with improved nitrogen retention [8] and reduced rates of hyperglycemia [10] compared with lower intakes of amino acids. In some neonatal intensive care units, amino acid intakes are increased more slowly, eg, by 0.5 g/kg/day each day, but there is no evidence that this slow advancement is beneficial. Our recommendations for VLBW infants are consistent with a European guideline [11] and supported by most literature [12].

Of note, adequate nonprotein energy intake (approximately 65 kcal/kg/day) is also required for optimum protein synthesis [8]. If sufficient nonprotein energy intake cannot be achieved, due to glucose or lipid intolerance, energy rather than protein will be rate-limiting for tissue anabolism and lower protein intakes should be given to avoid the acid load and ammonia/urea load that will result from catabolism of excess amino acids.

●Extremely low birth weight (ELBW) infants – For ELBW infants (<1000 g), somewhat lower amino acid intakes (eg, approximately 2.5 to 3.0 g/kg/day) may be appropriate during the first week of life. This is suggested by a trial in 499 infants with birth weight <1000 g who were randomized to receive a supplementary 1 g/kg/day of amino acid during the first five days of life or placebo in addition to their normal enteral and parenteral nutrition [13]. This resulted in average parenteral amino acid intake over the first five days of life of 3.4±0.6 g/kg/day in the supplemented group, compared with 2.6±0.6 g/kg/day in the standard PN group. At two years of age, there was no difference in the primary outcome (survival without neurodevelopmental impairment), but there were differences in secondary outcomes including a higher rate of moderate to severe neurodisability in children who had received the high-dose amino acids compared with those who received lower-dose amino acids (16.5 versus 8.6 percent; adjusted relative risk 1.95, 95% CI 1.09-3.48). There were no differences in mild neurodevelopmental impairment or in most other components of the Bayley III. The incidence of patent ductus arteriosus was more common in the higher-amino acid group.

The approach outlined above is slightly more cautious for ELBW infants than that outlined in the 2018 European guidelines for parenteral amino acid intake, which do not distinguish between ELBW and VLBW infants and recommend a targeted amino acid intake of 2.5 to 3.5 g/kg/day by day 2 [11] and maximum intakes of 3.5 g/kg/day [11,12].

●Larger infants – For larger infants (≥1500 g), lower parenteral protein intakes are appropriate. One recommendation is a maximum parenteral protein intake of 3 g/kg for 1500 to 2000 g and 2.5 g/kg for 2000 to 2500 g (compared with 3.5 g/kg for infants <1500 g) [12].

●Role of specific amino acids – Special "pediatric" amino acid solutions contain a higher concentration of essential amino acids and lower quantities of nonessential amino acids compared with adult formulations. The formulation is designed to produce plasma amino acid patterns that mimic those of healthy, breastfed neonates. Essential amino acids include isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. In the premature infant, other amino acids may be conditionally essential because the premature infant has a limited ability to synthesize them.

Cysteine and glutamate are not included in a standard pediatric amino acid solution. Considerations are:

•Cysteine – Many neonatal intensive care units add cysteine to PN for preterm infants. A typical dose is 20 to 40 mg of cysteine for each gram of amino acid. Although the data are contradictory [14,15], addition of cysteine to PN appears to improve nitrogen retention [16]. However, addition of cysteine also reduces the pH of the PN solution and increases metabolic acidosis in preterm infants, therefore increasing the need for acetate supplementation to normalize the pH [17]. The lower pH of the PN solution does have some benefits as it increases the solubility of calcium and phosphate and reduces the risk of precipitation.

•Glutamate – Because glutamate is a conditionally essential amino acid for preterm infants, it has been suggested that supplementation might improve growth or development. However, a few studies of glutamate supplementation of PN for preterm infants found no effects on neonatal growth, morbidity, or mortality [18,19]. One small study suggested that supplementation may increase brain white matter volume in later life [20].

Lipids — Lipids are an important component of PN for preterm infants. They are an important source of energy. They are also needed to prevent essential fatty acid deficiency, which can occur within the first week of life, and as early as the second day [21].

●Initiation – Lipids are typically initiated at 1 to 2 g/kg/day of intravenous lipid emulsion (ILE) [22]. ILE can be safely started on the first day of life [23]. Early (before day 5) introduction of lipids is not associated with any short-term differences in morbidity [24], but neither is it associated with improved growth or weight gain [24]. A minimum infusion of 0.25 g/kg/day is probably sufficient to prevent essential fatty acid deficiency in the short term [25].

ILE should be infused continuously over 24 hours/day. In the past, it was common to infuse the lipids over 15 to 22 hours daily, but continuous infusion of the lipid is better tolerated [26,27]. Rapid infusion of ILE is associated with risk for a syndrome of clinical decompensation, especially in infants [28-30]. This risk is minimized by intermittent monitoring of triglycerides and gradual advancement to target rates, as described below. Care should be taken to avoid more rapid infusions, even for a few hours. Maximal infusion rates, which depend on ILE type, are described in the manufacturer's prescribing information [31-33].

●Subsequent advancement – The dose of ILE should be advanced to 2 to 3 g/kg/day as tolerated, to ensure adequate caloric intake. Elevated serum triglyceride (TG) levels are relatively common in preterm infants, especially in the smallest and most immature infants, those receiving higher doses of intravenous lipids, or those with sepsis [34]. Therefore, we check TG once when the infusion reaches 2 g/kg/day lipids, and check again after any increase above this level, or when infants become septic. We adjust the ILE dose to maintain serum TG below approximately 200 or 250 mg/dL [34,35]. However, there is little clinical evidence that TG concentrations above this threshold are associated with morbidity or mortality [35]. For some infants who are chronically dependent on PN, it may be necessary to accept somewhat higher TG values (eg, up to 300 mg/dL). (See 'Hyperlipidemia' below.)

●Types of ILE – The ILE most commonly used in the United States is a soybean oil-based lipid emulsion with egg phospholipids (table 2). It is usually given as a 20% solution (Intralipid 20). Intralipid is also available as a 10% solution, but this formulation has fallen out of favor as the 20% solution is better tolerated due to its lower phospholipid content [36]. The soybean oil is a good source of essential fatty acids (linoleic acid and linolenic acid) but also contains phytosterols, which may be implicated in the development of PN-associated liver disease (PNALD). (See 'Liver toxicity' below and "Intestinal failure-associated liver disease in infants".)

In an effort to reduce the risk of liver toxicity, alternative forms of ILE have been developed including a fish oil-based lipid emulsion (Omegaven) or a combination of soybean, medium-chain triglyceride, olive, and fish oil lipid emulsion (SMOFlipid). These are now approved for use in this age group in the United States and Europe. (See 'Liver toxicity' below.)

Calcium and phosphate — Phosphorus and phosphate are often confused. Phosphorus, an element, is overwhelmingly found in biologic systems as phosphate ([PO₄]^3-). Phosphate is the form added to PN, the form that may precipitate with calcium, and the form measured in serum. One mole of phosphate contains 1 mole phosphorus, and 100 mg of phosphate contains approximately 32 mg of phosphorus. By convention, dietary requirements are usually expressed in terms of phosphorus. ILEs contain phospholipids, which provide a small but clinically insignificant amount of organic phosphate.

To optimize bone mineralization (especially in VLBW infants) and avoid hypophosphatemia, the PN for preterm infants should have relatively high concentrations of calcium and phosphate, as well as an optimal calcium:phosphate ratio. However, achievement of this goal is limited by PN admixture considerations, especially avoidance of calcium/phosphate precipitates.

●Target intake

•Calcium and phosphorus needs – To maximize bone mineralization, high concentrations of calcium and phosphate are generally recommended in PN for preterm infants. Target intakes are 65 to 100 mg/kg/day of elemental calcium and 50 to 80 mg/kg/day of phosphorus (table 1) [3,37] and can be achieved in most VLBW infants.

Evidence supporting these targets comes from a study in which increasing calcium intake from 45 mg/kg/day to 75 mg/kg/day and increasing phosphorus from 26.5 mg/kg/day to 44 mg/kg/day improved bone strength (measured by ultrasound speed of sound) [38]. Similar changes in intake were also associated with improved calcium and phosphorus retention [39]. Further increases in calcium (approximately 88 mg/kg/day) and phosphorus (approximately 80 mg/kg/day) intakes lead to greater calcium and phosphorus balance, and improved bone mineralization compared with lower parenteral intakes (65 and 60 mg/kg/day, respectively) [40].

•Calcium:phosphorus ratio – Bone mineralization is also affected by the ratio of calcium:phosphorus in PN. The optimal ratio is approximately 1.7:1 (mg/mg, or mass ratio), or 1.3:1 (molar ratio), as recommended by the American Society for Parenteral and Enteral Nutrition (ASPEN) [37]. Supportive data include a randomized trial, in which a ratio of 1.7:1 (mg/mg) was associated with improved calcium and phosphorus retention compared with ratios of 1.3:1 or 2:1 [41]. Other experts have recommended somewhat lower calcium:phosphorus ratios, ranging from 1.1:1 to 1.5:1 (mg/mg) [3].

Hypophosphatemia occurs in up to 60 percent of preterm infants receiving PN [42-44]. In many cases, this can be explained by low absolute intakes of phosphate (as little as 20 to 30 mg/kg/day phosphorus) [42,43], or by a high calcium:phosphate ratio (eg, 2:1 [calcium 100 mg/kg/day, phosphorus 50 mg/kg/day]) [44]. The phosphate requirement and optimal calcium:phosphorus ratio also may depend on the amino acid intake. This was suggested by one study, which found that hypophosphatemia and hypercalcemia were more likely if amino acids were initiated early without sufficient phosphorus (phosphate) intake [45]. These investigators proposed a formula to calculate the phosphorus requirement based on calcium and amino acid intake, but it is unclear if their findings are generalizable because the infants in this study had relatively low calcium and amino acid intakes.

Similarly, hypercalcemia in preterm infants usually is caused by low absolute intakes of phosphate, a high calcium:phosphate ratio, or delayed introduction of phosphate-containing PN (eg, beginning parenteral phosphate after 72 hours of life) [46]. It is important that calcium not be given without phosphate or phosphate without calcium for more than a day or two, because this can quickly lead to hyper- or hypocalcemia, and also because bone mineralization requires concurrent availability of both calcium and phosphate. If calcium or phosphorus are administered alone, ionized calcium and serum phosphorus should be assessed each day. Other less common causes of hypercalcemia in neonates are discussed separately. (See "Nephrocalcinosis in neonates", section on 'Hypercalcemia'.)

●Calcium and phosphate precipitation – One factor limiting the delivery of high amounts of calcium and phosphate is the risk of the formation of precipitates of bibasic calcium phosphate crystals that have been associated with pulmonary thromboemboli, which can be fatal [47-49]. The prediction of precipitation is complex. Precipitation becomes more likely as the amount of calcium and phosphate (and their product) increase.

Factors that reduce the risk of precipitation include:

•Lower pH [50]

•The addition of cysteine to PN (because this lowers pH) [51]

•Higher concentrations of amino acids [52]

•Use of the monobasic phosphate salt (which is more soluble than the bibasic salt) [52,53]

•Use of calcium gluconate (which is less likely to precipitate than calcium chloride) [54]

•Higher glucose concentration

•Prevention of excessive warming of the solution

•Using PN less than 24 hours after it was formulated

Newer organic phosphate sources may effectively remove the risk of precipitation [55,56]. In these forms, phosphate is part of an organic molecule (glycerol-1-phosphate, glucose-1-phosphate, or fructose-1, 6-phosphate), rather than a phosphate salt. The phosphate in these organic sources is unable to interact with calcium, and is released in the cell when the parent compound is metabolized. These products are not available in the United States.

Trace minerals — A variety of trace minerals are routinely added to PN for preterm infants (table 1). Many of these are probably not important if PN is a short-term bridge to full enteral nutrition. However, they become increasingly important the longer PN is continued.

Standard formulations of trace elements include zinc, copper, selenium, manganese and chromium. These are typically added to the PN within the first few days of life, while the PN is advanced to meet full nutritional needs. Iodine is not included in most trace element preparations and is rarely added to PN. If PN is continued for several months, iodine deficiency may develop, with associated hypothyroidism [57]. If topical iodine is used to disinfect the skin, premature infants may receive sufficient iodine or even excess iodine exposure (see "Thyroid physiology and screening in preterm infants" and "Acquired hypothyroidism in childhood and adolescence", section on 'Iodine deficiency'). Molybdenum is also not included in most trace element preparations, and routine supplementation in PN is not recommended by ASPEN [58,59].

Both zinc and copper deficiency are well described in preterm infants on prolonged PN containing suboptimal amounts of copper or zinc, although it typically takes many months for symptoms to develop [60]. Larger amounts of zinc may be needed in infants with intestinal losses, due to diarrhea or short bowel syndrome (see "Zinc deficiency and supplementation in children", section on 'Underlying medical conditions'). Symptomatic zinc deficiency has been reported in infants with abnormal losses or reduced absorption, or those receiving low amounts of parenteral zinc (40 mcg/kg/day) [61]. Similarly, copper deficiency has been reported in preterm infants with short bowel syndrome receiving 10 to 20 mcg/kg/day of copper in PN, likely due to a combination of low copper intake in PN and increased enteral losses [62].

For infants with cholestatic liver disease, the dose of copper and manganese should be reduced because these elements are excreted in the bile [63]. In these patients, we reduce the frequency of copper and manganese administration to twice a week. Of note, other components of PN (particularly magnesium sulfate and calcium gluconate) may contain significant amounts of manganese as contaminants [64].

For infants with impaired renal function, selenium should be eliminated or reduced because it is excreted renally.

Chromium and selenium are included in most formulations of trace elements. Limited evidence suggests that addition of chromium to PN may improve glucose tolerance [65], and that selenium supplementation of PN may reduce the rates of sepsis [63] or respiratory disease [66].

Iron is not routinely added to PN for preterm infants. There is little evidence of benefit for parenteral iron administration during the first few months of life in preterm infants [67]. As an example, iron dextran (0.25 mg/kg/day for the first five weeks of life) had no significant effect on hemoglobin concentration, growth, or the risk of sepsis [68]. Neonates who are treated with erythropoiesis stimulating agents may require additional iron supplementation, as discussed separately. (See "Anemia of prematurity (AOP)", section on 'Additional iron supplementation'.)

Vitamins — Premature infants need higher amounts of some vitamins than do term infants because of increased requirements for growth and/or greater losses. However, there are no commercially available vitamin formulations that are specifically designed to meet the needs of premature infants. Pediatric vitamin formulations generally meet or exceed the estimated vitamin needs for premature infants, as outlined in the table (table 3).

●Vitamin A – Vitamin A is a fat-soluble vitamin with multiple functions including effects on vision (corneal and conjunctival development, and phototransduction), immunocompetency, and cell differentiation. In premature infants, vitamin A is necessary for normal lung growth and maintaining the integrity of respiratory tract epithelial cells.

VLBW infants generally have lower stores of vitamin A than are considered optimal: one-third have hepatic stores <20 grams vitamin A/gram liver (g/g), indicative of deficiency, and three-fourths have stores of <40 g/g [69]. However, vitamin A is the most difficult vitamin to provide parenterally in sufficient quantities to VLBW infants without administering excessive quantities of other vitamins because of its loss through photodegradation and binding to the PN-containing bag and tubing [70]. Mixing the vitamin with intravenous lipid emulsion or use of retinyl esters helps to achieve greater plasma concentrations of vitamin A [71,72].

Clinical trials suggest that treatment of VLBW infants with supplemental vitamin A is associated with a modest benefit in reducing the risk of chronic lung disease [70]. However, the clinical relevance of these studies is unclear because they used a combination of parenteral and enteral vitamin A and were carried out in populations with high rates of chronic lung disease. (See "Bronchopulmonary dysplasia (BPD): Prevention", section on 'Vitamin A'.)

●Vitamin E – Vitamin E is a free-radical scavenger (antioxidant) that protects polyunsaturated fatty acids, a major structural component of the cell membranes, from peroxidation. Data from older randomized trials in premature infants suggested that vitamin E reduced the risk of bronchopulmonary dysplasia and retinopathy of prematurity. However, subsequent studies have demonstrated little or no risk reduction with the use of pharmacologic doses of vitamin E [73-78].

Some studies suggest that administration of vitamin E within 12 hours of birth reduced the incidence and severity of intraventricular hemorrhage (IVH) [79,80]. These studies are several decades old and have not been replicated. The suggested target plasma level of vitamin E for reducing IVH was >1 mg/dL by 24 hours of life and >2 mg/dL at three days of age [81]. These concentrations can be achieved with administration of the recommended dose of the available multivitamin formulations, which provide a vitamin E dose of 2.8 mg/kg/day, starting soon after birth (table 3).

●Water-soluble vitamins – The available multivitamin formulations generally provide more water-soluble vitamins than are needed by premature infants. The usual dosing of pediatric multivitamin formulations achieves adequate levels of thiamine (vitamin B1), riboflavin (vitamin B2), folate, and vitamin B12 [82]. There are several reports of elevated levels of plasma ascorbic acid (vitamin C), and riboflavin (vitamin B2) in premature infants receiving PN [83,84], but it is unclear whether or not these increased concentrations have any adverse effects.

Other parenteral nutrition components

●L-carnitine – L-carnitine supplements are typically added only for prolonged courses of PN (eg, more than approximately three weeks). L-carnitine is important for transport of fatty acids into the mitochondria. Early studies suggested that carnitine insufficiency can develop in preterm infants on PN, leading to impaired fatty acid oxidation and ketogenesis, and that these effects were reversible with carnitine supplementation [85,86]. However, randomized controlled trials and meta-analysis have found no effect of carnitine supplementation on apnea, duration of ventilatory support and hospital length of stay [87], triglyceride (TG) or free fatty acid levels [88], or weight gain [89], although small differences in ketogenesis have been reported [88].

●Heparin – We suggest adding heparin to most neonatal PN solutions, especially those running via a central venous catheter. The addition of heparin to neonatal PN may reduce the incidence of central venous catheter obstruction and/or catheter-related sepsis, based on limited evidence [90-93].

●Insulin – Addition of insulin to PN is not recommended for most premature infants, because the risk of hypoglycemia outweighs the potential benefits of insulin on growth, which are transient [2]. (See 'Hyperglycemia' below.)

Evidence against routine use of insulin infusions in preterm infants includes a study in which early administration of insulin (0.05 units/kg/hour) was associated with higher rates of hypoglycemia and no overall improvement in growth by 28 days of age, despite lower rates of hyperglycemia and less weight loss in the first week of life [94]. These findings overshadow those in an earlier pilot study, which reported reduced rates of hyperglycemia, higher insulin-like growth factor 1 levels, and improved short-term linear growth rates [95]. (See "Neonatal hyperglycemia".)

ADMINISTRATION — PN can be administered either through a central venous catheter (eg, peripherally-inserted central catheter or implanted port), or via a peripheral venous catheter or a "long line" (a catheter that is deeply inserted but not central).

Central catheters are generally preferable because they can be used with PN solutions of higher osmolarity compared with PN solutions for peripheral administration (which generally should be limited to an osmolarity of less than 900 mOsm/L) [37]. The use of a central catheter is also associated with higher nutrient intake and reduced need for line replacement, without any increase in infection risk [96].

The tubing used to administer PN should include an inline filter to exclude particulate matter such as precipitates. The filter is located as close to the infant as possible [97].

ADVERSE EFFECTS OF PARENTERAL NUTRITION — Adverse effects of PN can result from:

●Inadequate intake (or unbalanced intake) of nutrients

●Intolerance of PN (hyperglycemia, hyperlipidemia)

●Presence of toxic products or contaminants in PN

●Chemical modification of PN (eg, photo-oxidation)

●Complications of the central venous lines that are required to give high quality, concentrated PN

Certain adverse effects have more complex pathogenesis. In particular, the toxic effects of PN on the liver (known as PN-associated liver disease [PNALD], or intestinal failure-associated liver disease [IFALD]), are probably due to a combination of immature liver function, toxicity from certain components of parenterally administered lipid formulations, exacerbated by bacterial translocation or sepsis. (See 'Liver toxicity' below.)

Hyperglycemia — Hyperglycemia occurs during PN administration in more than one-half of preterm infants, and is especially common in those with extremely low birth weight or extreme prematurity [98]. Premature infants are prone to hyperglycemia due to a combination of factors:

●Impaired sensing of hyperglycemia

●Reduced insulin production and secretion

●End organ insulin resistance

●The glycemic effects of stress or sepsis, mediated by counterregulatory hormones such as catecholamines and glucocorticoids

●Failure of down-regulation of gluconeogenesis in the face of elevated blood glucose

Hyperglycemia in preterm infants is associated with adverse outcomes, including death and severe intraventricular hemorrhage (IVH) [98,99]. Treatment of hyperglycemia may decrease mortality in animal models [100], but there is little evidence of efficacy in preterm infants.

●Blood glucose target – For preterm infants, common practice is to try to maintain blood glucose above 47 mg/dL; there are no obvious reasons why blood glucose should be lower in preterm infants than in term infants. The American Society for Parenteral and Enteral Nutrition (ASPEN) recommends a minimum glucose threshold of >40 mg/dL [101]. However, the evidence for this target range is weak since no specific blood glucose threshold has been identified that is associated with worse clinical outcomes, or at which treatment of hyperglycemia improves outcomes. As an example, a randomized study of tight glycemic control (achieved with an insulin infusion of 0.05 units/kg/hour and target blood glucose 72 to 106) failed to demonstrate any change in mortality or morbidity compared with standard practice [102]. Although the tightly controlled group had greater weight and head circumference gains, they had lower length gain and increased incidence of hypoglycemia [102].

●Strategies – Strategies for maintaining blood glucose in the target range include the use of parenteral lipids and limiting glucose infusion rates, as well as insulin administration for severe hyperglycemia [101]. (See 'Other parenteral nutrition components' above.)

●Our approach – Our usual practice is to carefully assess and treat low blood glucose levels (<45 to 50 mg/dL), but to be tolerant of moderately elevated glucose levels (eg, blood glucose 250 to 350 mg/dL).

•We begin parenteral protein and lipids, and enteral feeds, as soon as possible after birth.

•If blood glucose levels exceed 250 mg/dL, we reduce glucose infusion rates in the short term, but generally not below a glucose infusion rate of 5 to 8 mg/kg/minute (or 7.2 to 11.5 g/kg/day of dextrose), which is the basal glucose requirement for preterm infants.

•If blood glucose concentrations are consistently above 250 to 400 mg/dL despite reducing the glucose infusion rate, we consider treatment with insulin.

However, our own anecdotal experience is that the need for insulin treatment is not generally needed if parenteral protein and lipid are started early, and if enteral feeds are started early and advanced appropriately (ie, quite rapidly).

If insulin is required, the initial dose is typically 0.05 to 0.1 units/kg/hour, adjusted to target a blood glucose of 150 to 250 mg/dL. However, we use insulin only in selected cases with persistent severe hyperglycemia. This is because there is no clear evidence that short- or medium-term exposure to moderate hyperglycemia is detrimental in preterm babies, and the use of insulin is associated with greater risk of hypoglycemia, which is clearly detrimental to preterm infants. Hypoglycemia is usually accompanied by increases in alternate energy substrates (free fatty acids and ketones); however, hypoglycemia due to insulin therapy is associated with low free fatty acids and ketone levels, which may make it particularly damaging. (See 'Other parenteral nutrition components' above.)

(See "Neonatal hyperglycemia", section on 'Management'.)

Hyperlipidemia — Target triglyceride (TG) concentrations for infants receiving intravenous lipid emulsion (ILE) are typically <250 mg/dL, if possible [34,35]. Elevations above this threshold are uncommon unless lipid infusion rates are >2 g/kg/day, or in very preterm or low birth weight infants, or if sepsis develops. TG levels up to 250 or 300 mg/dL may be acceptable in some cases. (See 'Lipids' above.)

Limited data suggest that ILE may reduce bacterial clearance in septic infants [103] and might be associated with an increased risk of chronic lung disease [104]. Data are conflicting as to whether ILE displaces bilirubin from albumin [22,104]. If so, excessive concentrations of ILE might increase the adverse effects of hyperbilirubinemia. The long-term effects of ILEs are unclear. One study suggested that individuals who received ILE during infancy had increased aortic stiffness and decreased cardiac function in young adults compared with controls with similar perinatal characteristics [105], but this remains to be confirmed.

Liver toxicity — The ILE most commonly used in the United States is a soy-based emulsion (Intralipid). However, alternative ILEs are increasingly used and are now approved for this age group in the United States and Europe [106-108]. This is largely driven by concerns about the phytosterol content of soybean oil and its potential relationship to the development of IFALD, also known as PNALD. (See "Intestinal failure-associated liver disease in infants".)

In light of these concerns, it seems prudent to limit exposure to soy-based ILE as much as possible and to use alternative forms of ILE in selected patients (table 2). To do this, our personal practice is:

●Limit Intralipid infusions to 2 to 3 g/kg/day, when possible, as long as this is compatible with the provision of adequate parenteral calories.

●Reduce Intralipid to 1 g/kg/day in infants who have developed IFALD, or are at very high risk of doing so, such as those who have had extensive gastrointestinal resections and risk of short bowel syndrome. This strategy is appropriate only if it is compatible with the provision of adequate parenteral calories.

●Use alternative lipids with lower phytosterol levels (eg, a mixed soybean, medium-chain triglyceride, olive, and fish oil lipid emulsion [SMOF]) for selected infants at high risk of developing IFALD, such as those with severe short bowel syndrome who are likely to require long-term PN support.

Clinical evidence regarding SMOF ILE for prevention of IFALD is limited, and practice varies regarding selection of infants for this form of ILE. A reasonable approach would be to use it in infants at high risk of IFALD whose direct bilirubin is >2 mg/dL. SMOF ILE is available in Europe and the United States. (See "Intestinal failure-associated liver disease in infants", section on 'Composite lipid emulsions'.)

●Use a fish oil-based lipid emulsion (eg, Omegaven) for infants with established IFALD (direct bilirubin >2 mg/dL for more than two to four weeks) who are likely to remain on PN for at least another four weeks. (See "Intestinal failure-associated liver disease in infants", section on 'Fish oil-based lipid emulsions'.)

Aluminum toxicity — Aluminum is a widespread contaminant of PN components, especially calcium gluconate, phosphate salts, and vitamin C [109]. Toxicity is most likely due to deposition in bone and brain in preterm infants [109]; limited evidence suggests that preterm infants who receive higher intakes of parenteral aluminum may have worse neurodevelopment as toddlers and lower bone mineralization as adolescents [110,111]. Although reduction in aluminum load is clearly desirable, it is difficult to achieve using available PN products. The FDA recommends that PN contain less than 25 mcg/L of aluminum, but this goal probably is infrequently achieved in clinical practice [109,112]. (See "Intestinal failure-associated liver disease in infants", section on 'Pathogenesis'.)

Calcium/phosphate precipitates — Precipitates of bibasic calcium phosphate crystals occasionally develop in PN and have been associated with pulmonary thromboemboli, which can be fatal, or interstitial pneumonitis [47-49]. This can be prevented by careful management of the PN admixture, including limits on concentrations of calcium, phosphate, and their product. (See 'Calcium and phosphate' above.)

PRESCRIBING PARENTERAL NUTRITION AND ADJUSTING FOR FEEDS

●Prescribing approaches – More than 750,000 prescriptions for neonatal PN are written in the United States each year annually, and they are an important source of medical errors [113].

One approach to reducing these errors has been to use a limited number of standardized PN solutions for infants rather than totally individualized solutions. The advantage of this approach was demonstrated in a study from Australia that used three main PN solutions (a starter solution, a preterm infant solution, and a term infant solution) with two option variants (higher sodium or lower glucose for preterm infants) [114]. Use of these standard solutions resulted in suboptimal protein and energy intakes during the first few days of life, but adequate protein and weight gain thereafter [115]. Similarly, another study reported that use of standard solutions was associated with modest weight loss in the first week of life [116]. The relative success of standard solutions may in part depend on who is doing the individualized prescribing. The optimal approach is probably individualized PN prescription by a pharmacist or other PN expert, where available, rather than the use of standardized solutions [117].

An alternative approach is the use of computer-supported prescribing, which may reduce the time taken to prescribe PN and reduce errors, while also improving intake and growth [118]. However, the benefits may be modest. Clinical studies of this approach reported that computer-supported prescribing increased the number of babies receiving targeted nutritional intake from 5 to 25 percent [119], or reduced the time taken to achieve targeted nutritional intakes from 8.7 to 5.9 days [120].

Another issue is whether PN should be prescribed as unit/kg/day (ie, g, mg or mEq/kg/day, depending on the component), or as a concentration and volume (infusion rate). Considerations are:

•Units/kg/day prescribing – The American Society for Parenteral and Enteral Nutrition (ASPEN) strongly supports this approach to prescribing PN [121]. This ensures optimal nutrient intakes when performed by an expert. The main disadvantage approach is that it requires frequent calculations and reformulation of PN because the relative contribution of enteral feeds and PN changes daily, or more often. As feeds increase, two adjustments are needed: one to reduce the prescribed parenteral intake as the enteral intake increases, and one to adjust for intolerance (or glucose or lipids) or to adjust electrolytes, calcium, and phosphate in response to biochemical monitoring (table 4).

•Concentration/volume prescribing – We prefer to this method because we find it to be simpler, more efficient, and less prone to error. This approach uses a "typical" PN solution (table 5), which is designed to meet the nutritional needs of the infant if given at a rate of 130 mL/kg/day of PN, with 10 mL/kg/day of 20 percent Intralipid. Once an infant can tolerate trophic feeds (20 mL/kg/day), with full PN (130 mL/kg/day and Intralipid at 10 mL/kg/day), it is easy to gradually transition to enteral feeds by exchanging PN for enteral nutrition, mL for mL, until the target for full feeds is reached (160 mL/kg/day of fortified human milk or preterm formula). It is still necessary to adjust electrolytes, calcium, and phosphate in response to biochemical monitoring, but the concentration of nutrients remains the same, and only the PN rate is modified as enteral feeds advance. (See "Approach to enteral nutrition in the premature infant".)

●Adjusting for advances in enteral feeds – Regardless of the method used for PN prescribing, enteral nutrition should be steadily advanced to the target volume of 150 to 170 mL/kg/day of fortified human milk or preterm formula, as tolerated by the infant. More rapid advancement of feeds (30 mL/kg/day) seems to be as well tolerated and as safe as slower advancement (15 to 20 mL/kg/d) and can shorten the time to reach full feeds to within one to two weeks. (See "Approach to enteral nutrition in the premature infant", section on 'Infants requiring tube feeding'.)

MONITORING — There is little robust evidence to guide the frequency of biochemical monitoring, but our typical practice is:

●Blood glucose – Checked at least twice daily while on intravenous fluids and more frequently if needed to maintain blood glucose in the target range.

●Electrolytes, blood urea nitrogen, creatinine – Initially check every one to two days; later, two to three times a week. Very low birth weight (VLBW) infants may require more frequent measurements to guide fluid management.

●Calcium, phosphate, alkaline phosphatase – Check after approximately one week of PN, then every second week, or more frequently if there are concerns about the overall adequacy of calcium and phosphate intake. We use the reference range for preterm infants provided by the reporting laboratory and do not correct for hypoalbuminemia. (See 'Calcium and phosphate' above.)

●Ionized calcium – Check after 12 to 24 hours, and as required.

●Triglycerides – A reasonable approach is to measure triglycerides (TG) once on 2 g/kg/day lipids, and after any increase above this level, or if the infant becomes septic. Common practice is to try to keep TG below approximately 200 to 250 mg/dL. (See 'Lipids' above.)

●Liver tests – Check alanine aminotransferase, aspartate aminotransferase, and cholestasis markers (total and direct bilirubin, gamma-glutamyl transferase) after approximately one week of PN, then every one to two weeks.

●Albumin, prealbumin – These are not measured routinely; they are typically only measured in response to concerns about suboptimal growth.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nutrition support (parenteral and enteral nutrition) for neonates including preterm infants".)

SUMMARY AND RECOMMENDATIONS

●Initiation of parenteral nutrition (PN) – For preterm infants, PN should be started as soon as possible after birth, ideally on the first day of life. The initial targets for nutrient composition are designed to prevent catabolism and hypocalcemia. The initial prescription should include (table 1) (see 'Parenteral nutritional requirements' above):

•Sufficient amino acid and energy to prevent catabolism (minimum protein 1.5 g/kg/day and energy 30 to 40 kcal/kg/day)

•Sufficient calcium to prevent hypocalcemia (at least 25 mg/kg/day)

•Intravenous lipid emulsion (ILE), starting on the first or second day of life, to prevent essential fatty acid deficiency and to provide additional energy

●Subsequent PN advancement – Nutrient composition in the PN is quickly advanced over the first 24 to 48 hours of life to provide full nutrition for optimal weight gain, protein deposition, and bone mineralization (full PN) (table 1). Adjustments include:

•Increase the amino acid intake and energy content to support growth; optimal targets depend on birth weight. (See 'Amino acids' above and 'Energy requirements' above.)

•Advance the ILE to approximately 2 to 3 g/kg/day, while titrating the infusion to avoid hyperlipidemia and maintain appropriate nonprotein energy intakes. (See 'Lipids' above and 'Hyperlipidemia' above.)

•Add phosphate, and advance the calcium concentration. For optimal bone mineralization, PN for preterm infants should have relatively high concentrations of calcium and phosphate, as well as a calcium:phosphate ratio of approximately 1.7:1. However, achievement of this goal is limited by PN admixture considerations, especially avoidance of calcium/phosphate precipitates, which can cause pulmonary emboli. (See 'Calcium and phosphate' above.)

•Titrate the glucose infusion as needed to keep the whole blood glucose in the target range. If this prevents meeting caloric goals for greater than two to three days, insulin infusion should be considered. (See 'Hyperglycemia' above.)

●Feeding advancement – Enteral nutrition (ideally of human milk) should be started on the first day of life at low volume (trophic feeds, at 20 mL/kg/day), then gradually advanced, while PN is decreased. The target for full feeds is 160 mL/kg/day of fortified human milk or preterm formula. (See 'Prescribing parenteral nutrition and adjusting for feeds' above and "Approach to enteral nutrition in the premature infant", section on 'Infants requiring tube feeding'.)

●Laboratory monitoring – Laboratory monitoring is required to adjust the contents of PN to avoid excesses or deficiencies of any given nutrient and to monitor for PN-associated complications. (See 'Monitoring' above.)

●Adverse effects – Adverse effects of PN include hyperglycemia, hyperlipidemia, line infection, and sepsis. Prolonged use of soy-based ILE in premature infants is associated with development of cholestatic liver disease. For infants who develop liver disease, strategies include limiting total intake of intravenous lipids and use of alternative forms of ILE. (See 'Adverse effects of parenteral nutrition' above and 'Liver toxicity' above and 'Lipids' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard J Schanler, MD, who contributed to earlier versions of this topic review.