Clinical aspects

Description

Carbohydrates. Glucose is an essential source of energy and the most commonly used carbohydrate in total parenteral nutrition. Carbohydrates should provide approximately 35% of daily calorie needs and approximately 60% of nonprotein energy (15). Glucose infusion should begin at 6 to 8 mg/kg per minute soon after birth and should be adjusted to achieve blood glucose concentrations between 45 to 120 mg/dL (48; 43). Commonly used dextrose solutions are 5% and 10%. Higher dextrose concentration solutions are typically required by infants of diabetic mothers in the first few days of life. Most patients can tolerate an increase in glucose infusion rate (GIR) of 1 mg/kg per day or 2.5% to 5% dextrose per day. Intravenous glucose infusion rates greater than 10 to 11 mg/kg/min almost invariably lead to hyperglycemia. The definition of hyperglycemia is not very clear for the neonatal population. Plasma glucose more than 150 mg/dL has been suggested as a reasonable threshold (94). Excessive glucose infusion rates have many adverse effects, including increased energy expenditure, increased oxygen consumption, increased carbon dioxide production, tachypnea, fatty infiltration of the heart and liver, and excessive fat deposition (which may possibly lead to obesity) (19). High glucose levels (> 360 mg/dL) can cause significant osmolar changes resulting in dehydration, electrolyte derangements, and cerebral damage. Necrotizing enterocolitis, retinopathy of prematurity, intraventricular hemorrhage, and increased mortality are other complications with hyperglycemia (42; 49; 03). Insulin has been used in conjunction with a higher GIR to allow more energy intake under the assumption that this combination would promote growth and glycogen storage. According to Hay, this combination is ineffective while contributing to further organ and adipose tissue fat deposition (43). In most cases, insulin should only be used when decreasing the GIR to 4 or less; it does not resolve hyperglycemia. Another effective way to reduce hyperglycemia might be infusion of higher rates of amino acids, which have been shown to improve glucose tolerance in very low birth weight infants. Use of insulin infusions to prevent or reduce hyperglycemia has resulted in modest reduction in hyperglycemia but at the cost of an increased frequency and severity of hypoglycemia (18). The safest approach in treating hyperglycemia is to lower glucose infusion rate rather than add insulin due to the risks associated with it (63). Tight blood glucose control or prophylactic insulin and/or glucose treatment showed more episodes of hypoglycemia or mortality in extremely low birth weight (ELBW) infants. The balance of risks and benefits of insulin treatment of hyperglycemia in preterm neonates remains unclear (09; 04).

Protein. The major goal in providing amino acids after birth is to prevent negative nitrogen balance, reduce catabolism, and promote protein accretion. Although there is no direct method for measuring protein needs, studies have shown that endogenous loss of protein (in urine, feces, skin cells, and secretions) is 1g/kg per day if no supplemental protein is given (32). As predicted, daily protein accretion of a fetus at about 28 weeks of gestation is approximately 2 g/kg; at least 3 to 3.5 g/kg of amino acids is needed to promote protein accretion while allowing for the obligatory loss (110). Protein provides 4 kcal/gram and should supply 12% to 17% of total daily calories. In premature infants, the amino acid should start on the first postnatal day with at least 1.5 g/kd/d to achieve an anabolic state; from day 2 onwards, it should be between 2.5 to 3.5 g/kg/d and should be accompanied by nonprotein intakes of more than 65 kcal/kg/d (105).

Amino acids are essential not only for growth but also for metabolic signaling, protein synthesis, and protein accretion (43). Amino acids are also needed to promote solubility of substrates and as an energy source to improve tolerance of lipid infusion.

Studies now support that providing 2 to 3.5 g/kg per day of amino acid shortly after birth is well tolerated and improves protein accretion (98; 46; 96; 44). There are now more data to support even higher intakes of up to 4 g/kg/day during the first week (28; 68). However, infusing amino acids of 4 g/kg/day by day 3 of life in very premature infants has been associated with high urea and ammonia concentrations (12). Moreover, at 18 months corrected age, Bayley Mental Developmental Index scores were lower with the high amino acid intake, but improved by 24 months (13). Weight, height, and head circumference were lower than in infants with standard amino acid intakes. Many comparative studies did not show a difference in the pH or base deficit between groups taking different AA doses (the initial dose of 0 to 3 g/kg/day with a target range of 2.4 to 4 g/kg/day) (Porcelli and Sisk 2002; 96; 47; 12; 21; 101). Administering a high dose (> 3 g/kg/day) or an early dose (< 24hrs) of parenteral amino acid is safe and well tolerated, but does not offer significant benefits with regard to growth (58). Per ESPGHAN guidelines, parenteral amino acid intakes above 3.5 g/kg/d should only be administered as a part of clinical trials (56). However, a 2017 study showed increased non-lactic metabolic acidosis in very premature infants who received enhanced early nutrition according to recent guidelines (17). Special attention should be paid to calcium and phosphorus levels in preterm infants during first week of life receiving high amino acid infusion. A study by Bonsante and colleagues highlights the influence of early AA intake on calcium and phosphorus homeostasis (16). Preterm infants (gestational age less than or equal to 33 weeks) were divided into 3 groups according to their mean AA intake during the first week of life. The incidences of hypophosphatemia and hypercalcemia, respectively, were increased in the high (greater than 2 g/kg/day of mean AA intake) AA intake group relative to the moderate (1.5 to 2 g/kg/day) and low (less than 1.5 g/kg/day) intake groups (18).

Emphasis should be placed on providing optimal protein and energy during the first week of life (92). In extremely low birth weight infants (less than 1000 g), increased intake of protein and energy in the first week was associated with higher Mental Developmental Index Scores (92) and lower likelihood of length growth restriction. In fact, early administration of amino acids improves the weight of preterm infants (103), decreases postnatal growth restriction (28), and improves postnatal head growth (68). Studies have found improved long-term outcomes, such as growth and neurodevelopment. Poindexter and colleagues found significant improvement in growth parameters (weight, length, and head circumference) at 36 weeks postmenstrual age in the infants who received early amino acids, but no difference was found in growth or in neurodevelopmental outcome at 18 months of age (79). Van den Akker and colleagues found no difference in growth, but found a neurodevelopmental advantage at 2 years corrected for boys who received amino acids from the first day of life compared to the infants who received glucose alone (104). Stephens and colleagues reported a retrospective analysis of 150 extremely low birth weight infants and found a positive association between protein intake in the first week of life and scores on the Bayley Mental Developmental Index at 18 months corrected age.

Osborn and colleagues studied higher versus lower amino acid intake on growth and disability-free survival for newborn infants. Higher amino acid intake (2 to 3.5 gm/kg/day) was associated with positive nitrogen balance, earlier regain of birth weight, and increased head circumference growth at hospital discharge. Higher amino acid intake was not associated with effects on days to full enteral feeds, late-onset sepsis, necrotizing enterocolitis, chronic lung disease or severe intraventricular hemorrhage, and mortality before hospital discharge (74). However, a randomized controlled trial by Balakrishnan and colleagues found that high-dose amino acid supplementation (3 to 4 g/kg/d) starting at birth was not associated with improved growth or neurodevelopmental outcomes (08).

Despite the increase in protein nutrition, parenteral nutrition-dependent very premature infants are still at risk for deficiency for the conditionally essential amino acids, particularly tyrosine, glutamine, cysteine, and arginine (97). Even with supplementation to traditional amino acid solutions using a standardized, concentrated, added macronutrients parenteral (SCAMP) nutrition regimen, very premature infants did not achieve conditionally essential amino acid levels that reached reference ranges (67). A Cochrane review of glutamine supplementation, however, did not demonstrate any effect on mortality or major neonatal morbidities including incidence of sepsis, necrotizing enterocolitis, or neurodevelopmental outcomes (66).

The most common amino acid solutions available for infusion are TrophAmine® (Kendall-McGraw Laboratories, Irvine, CA), Premasol (Baxter Healthcare Corporation, Deerfield, IL), and Aminosyn-PF® (Abbott Laboratories, North Chicago, IL). These solutions are available in 6% and 10% solutions and contain taurine, tyrosine, histidine aspartic acid, and glutamic acid and lower concentrations of methionine, glycine, and phenylalanine than that found in solutions intended for older patients (07). Infants receiving these formulations have greater weight gain and a more positive nitrogen balance than infants receiving standard adult amino acid solutions. The commercial solutions do not contain cysteine. Cysteine must be added during compounding, as it is precipitates over time in solution, and it has shown to improve nitrogen balance in premature infants. A 2006 Cochrane review found that growth was not affected by cysteine supplementation, but nitrogen retention was significantly improved (91). Cysteine also improves the solubility of calcium and phosphorus in total parenteral nutrition by changing the pH, and it improves the retention of glutathione, which is an important antioxidant (85; 20). Another amino acid worth mentioning is arginine. Arginine is important in the production of nitric oxide and glucose homeostasis (05). Amin and colleagues performed a randomized controlled trial on arginine supplementation. They randomized 152 premature infants to receive arginine or placebo. They found that arginine supplementation was well tolerated and resulted in a decreased incidence of all stages of necrotizing enterocolitis.

Lipids and essential fatty acids. Lipids are iso-osmolar and provide more calories per gram—9 kcal/gram—than protein and carbohydrates. Lipids should provide 25% to 40% of nonprotein parenteral nutrition calories. Lipid emulsion contains triglycerides (soybean oil or safflower oil), egg yolk phospholipid (for emulsification), and glycerol to achieve isotonicity. It provides energy and essential fatty acids, both of which are important for growth and neurodevelopment. Essential fatty acids (linoleic [omega-6] and alpha linolenic acid [omega-3]) are precursors for the synthesis of long chain polyunsaturated fatty acids (PUFA), especially (EPA and DHA), which play a structural role in biological membranes and are involved in retinal and brain development.

In utero, lipids are obtained from the maternal diet and transferred via the placenta to the fetus in the form of PUFA. Of the PUFA delivered, the placenta transfers docosahexaenoic acid (DHA) more so than other fatty acids (linoleic acid, linolenic acid, and arachidonic acid). DHA constitutes 50% of neuronal plasma membranes and is the only n-3 PUFA found in significant amount in the retina and brain.

After delivery, lipids should be started at a rate of 0.5 to 1 g/kg/day to avoid essential fatty acid deficiency (43; 52). Recommendations suggest starting 1 g/kg/day on the first day, incrementally advancing to a goal of 3 to 4 g/kg/day at the end of the first week (54), provided the triglyceride level remains less than 175 to 200 mg/dL (07). There is no evidence that gradual increments in the rate of infusion of lipids improves fat tolerance; however, higher amounts of lipids (2 to 3 g/kg/d) on the first day of life may result in hyperlipidemia (107). In preterm and term infants, parenteral lipid intake should not exceed 4 g/kg/d (56). If the triglyceride level is elevated, lipids need to be decreased according to the serum level of the triglycerides; however, it should be continued at lowest possible rate (0.25 g/kg/d) to prevent essential fatty acid deficiency.

There is evidence that early introduction of parenteral lipids during the first week is safe and well tolerated in very low birth weight infants (106; 56). It is also associated with weight gain and could improve early nutritional support for these preterm neonates (39).

Lipid emulsion are available in 10%, 20%, and 30% solutions. The 10% and 20% were designed for direct infusion, and the 30% for use in 3-in-1 preparations. Phospholipids are believed to inhibit lipoprotein lipase; therefore, the 20% lipid emulsions are better tolerated than 10% due to lower total phospholipid and liposome content per gram of triglyceride (07). Pure soybean emulsions may provide less balanced nutrition than composite emulsions. Soybean emulsions contain a high concentration of essential fatty acids (approximately 60% of total fatty acids) with a ratio of w-6 to w-3 fatty acids of 8:1, but they lack appreciable amounts of long-chain polyunsaturated fatty acids. In addition, they contain low amounts of alpha-tocopherol, which can contribute to increased peroxidation of the parenteral polyunsaturated fatty acids. Soybean emulsions contain a high ratio of w-6 to w-3 fatty acids, which, in turn, leads to lesser proportions of w-3 fatty acid derivatives docosahexaenoic acid and eicosapentaenoic acid. Both docosahexaenoic acid and eicosapentaenoic acid are important substances of neural and retinal development with antiinflammatory properties (90). Soybean oil–based lipid emulsions are rich in proinflammatory w-6 long-chain polyunsaturated fatty acids and phytosterols; both are known to trigger parenteral nutrition–associated liver disease (84). For parenteral nutrition lasting more than 5 days, pure soy emulsions should no longer be used, and composite emulsions with or without fish oil should be the first choice. These composite lipid emulsions contain higher amounts of vitamin E and less phytosterols (100).

Lipids can be infused separately from amino acid/dextrose solution or combined in a 3-in-1 mixture (fats/proteins/dextrose in the same solution). According to a study by Colomb and colleagues, 3-in-1 total nutrition formula was more manageable and easier to administer (27). It was also shown to be more cost-effective and requires less nursing time than conventional peripheral parenteral nutrition. Despite these benefits, a separate lipid delivery system is preferred due to better tolerance and the ability to cycle lipids off and on without interrupting the amino acid/dextrose infusion. Additionally, the Centers for Disease Control has recommended against the use of the 3-in-1 formula due to issues of precipitation of components, especially in neonates.

In addition to their nutritional role, lipid emulsions can influence numerous pathophysiological processes including oxidative stress, immune response, and inflammation. The benefits of fish oil come from n-3 PUFA concentrations, which are rich in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and have specific anti-inflammatory effects. They are also devoid of phytosterols, which are thought to contribute to parenteral nutrition associated liver disease (PNALD).

In preterm infants receiving soybean oil derived lipid emulsion, DHA and arachidonic acid (ARA) levels (derived from EPA) decline rapidly after birth. Low levels of these fatty acids are associated with morbidity, namely chronic lung disease and late onset sepsis (62; 86). Studies using fish oil lipid emulsions (rich in n-3 PUFA) have suggested that increasing the amount of DHA through the use of fish oil is well tolerated, can decrease the risks of late onset sepsis, hyperbilirubinemia, and cholestasis, and can improve growth in very low birth weight neonates (83; 107). Infants who received lipid minimization with soybean oil emulsions, but not those who received lipid minimization with fish oil emulsions, are at high risk of biochemical essential fatty acid deficiency and slower weight gain (36). Evidence also demonstrates reversal of established hepatic dysfunction (55; 78), but there was no prevention (38). Currently there are 3 lipid emulsion products containing fish oil: Omegaven® (Fresenius Kabi, Germany), with 10% fish oil; Lipoplus®/Lipidem® (B. Braun, Germany), containing 50% medium chain triglycerides (MCT), 40% soybean oil, and 10% fish oil; and SMOFlipid® (Fresenius Kabi, Germany), containing a mixture of 30% soybean oil, 30% MCT, 25% olive oil, and 15% fish oil (53). Newer SMOF lipid mixtures are well tolerated by premature infants and effective in optimizing fatty acid profiles, reducing liver injury and improving direct bilirubin levels in case of parenteral nutrition associated liver disease (83; 78). In a 2014 Australian study comparing SMOFlipid to olive oil lipid emulsion [(ClinOleic® 80% olive oil and 20% soybean oil) (Baxter, Deerfield, IL)], SMOFlipid was well tolerated and showed beneficial effects in terms of reduction of oxidative stress by reducing lipid peroxidation levels (33). Many newborn intensive care units have started replacing soy-based lipid formulations with Smoflipid^® (w-3 enriched lipid emulsion) as the primary component in parenteral nutrition for preterm infants (25).

However, a Cochrane review by Kapoor and colleagues found no benefit of mixed lipid emulsions (LE) (MCT-olive-fish-soy oil-lipid emulsions; MCT-fish-soy oil-lipid emulsions; olive-soy oil-lipid emulsions; and borage-soy oil-lipid emulsions) over pure soy oil based lipid emulsions in terms of death, growth, bronchopulmonary dysplasia (BPD), sepsis, retinopathy of prematurity greater than stage 3, and parenteral nutrition associated liver disease (50).

Macronutrients, vitamins, and micronutrients. Creating parenteral nutrition solutions that mimic enteral nutrition is difficult due to solubility issues, incompatibility issues, photo-degradation of components, and the lack of knowledge of definite levels of nutrients to meet the demands of patients. Essential for complete nutrition are macro minerals (electrolytes), vitamins, and micro minerals (trace elements).

Two parenteral vitamin solutions are available for use in infants in the United States: MVI Pediatrics® (AstraZeneca Pharmaceuticals) and INFUVITE® Pediatric (Boucherville, Quebec, Canada). Both contain water and fat-soluble vitamins. Of particular importance in patients with intestinal failure and those on parenteral nutrition are the fat-soluble vitamins A, D, E, and K (57). The micronutrients such as zinc, copper, selenium, and iodine should be added to parenteral nutrition in very low birth weight infants within a few days after birth. Parenteral supplementation of iron, manganese, chromium, and molybdenum is rarely needed in very low birth weight infants but should be considered in patients with intestinal failure that requires prolonged total or near total parenteral nutrition. Parenteral iron requirements are estimated to be 200 to 250 mcg/kg/d in preterm infants and 50 to 100 mcg/kg/d in term infants. Iron supplementation should be preferably given via enteral route (35).

Trace elements are necessary in many aspects of cell function: enzyme activity, protein and lipid metabolism, immune and inflammatory healing modulation, thyroid and other endocrine functions, and development of the central nervous system.

Table 1. Suggested Parenteral Intakes of Trace Minerals in Infants and Children

Element	Preterm Mcg/kg per day	Term Mcg/kg per day	Children Mcg/kg per day (maximum, Mcg/kg per day)
Zinc* Copper** Selenium*** Chromium*** Manganese** Molybdenum*** Iodide****	400 20 2 0.20 1 0.25 1	250 < 3 mo 20 2 0.20 1 0.25 1	50(5000) 100 ≥ 3 mo 20(300) 2(30) 0.20(5.0) 1(50) 0.25(5.0) 1(1.0)

*Standard trace element preparations do not supply the high requirement of premature infants, so it should be added to parenteral fluid.

**Omit in patients with obstructive jaundice, as manganese and copper are excreted primarily in bile. Copper status should be monitored in patients with cholestasis if not provided in total parenteral nutrition.

***Omit in patients with renal dysfunction.

Available concentrations of molybdenum and manganese are such that dilution of the manufacture’s product may be necessary. Neotrace® (Lymphomed Co, Rosemont, IL) contains a higher ratio of manganese to zinc than suggested in this table (ie, zinc: 1.5 mg, and manganese: 25 mcg in each mL).

Adapted from (52)

Table 2. Daily Electrolyte and Mineral Requirement for Pediatric Patients

Electrolyte	Preterm neonates	Infants/children
Sodium Potassium Calcium Phosphorus Magnesium Acetate and chloride	2-5 mEq/kg 2-4 mEq/kg 2-4 mEq/kg 1-2 mEq/kg 0.3-0.5 mEq/kg As needed to maintain acid-based balance	2-5 mEq/kg 2-4 mEq/kg 0.5-4 mEq/kg 0.5-2 mEq/kg 0.3-0.5 mEq/kg As needed to maintain acid-based balance

Adapted from (64)

In children receiving parenteral nutrition, especially preterm infants, supplementation of electrolytes should be adjusted according to their serum values.

The goal is always to start enteral nutrition, even small trophic feeds or “minimal enteral feeds,” as soon as the gastrointestinal system will allow.

To date, nearly all studies have shown that minimal enteral feeding approaches promote the capacity to feed enterally (43). According to a Cochrane review, infants given trophic feeds had a reduction in days to full feeding, in days that feedings were held, and in length of hospital stay (102). Enteral nutrition has been shown to increase exocrine pancreatic secretion in response to gastrointestinal hormones. Because parenteral nutrition bypasses the gastrointestinal system and is continuous rather than off/on, as in bolus enteral feeding, hormone excretion mimics elevated postprandial levels for extended periods of time. Continuously elevated levels of hormones in patients on prolonged total parenteral nutrition have been suspected to reset the hormone “set point” and lead to BMI increasing year after year in these children (99). Enteral nutrition has also been shown to increase gastric parietal cell mass in patients compared with parenteral nutrition, and a lack of enteral nutrition has been shown to decrease gut associated lymphatic tissue, therefore, increasing the risk for inflammatory disease states (45).

Indications

Parenteral nutrition should be provided as soon as possible after the infant’s birth if enteral nutrition is not possible or will be inadequate. Providing early parenteral nutrition especially in premature infants has shown to improve nitrogen balance and extra uterine growth restriction. Although enteral nutrition is the preferred route, parenteral nutrition is of paramount importance in infants with gastrointestinal disorders such as intestinal atresia, abdominal wall defects (omphalocele, gastroschisis), necrotizing enterocolitis, and short bowel syndrome, and parenteral nutrition is important in the immediate newborn period when enteral nutrition is not feasible because of unstable medical condition.

Contraindications

Parenteral nutrition is contraindicated in patients with functioning bowel who can tolerate enteral nutrition at a level to provide adequate energy and other nutrients for growth.

Outcomes

A coordinated nutritional support team is a key factor to optimize parenteral nutrition, maintain accuracy of the parenteral nutrition delivered, decrease adverse effects, and improve outcome to minimize hospital stay and cost (52). This specialized team includes physicians, dietitians, nursing and ancillary staff, pharmacists, and surgical staff. Strategies to reduce errors, improve quality of care, and provide optimal nutrition have proven to be effective. These processes include offering nutritional education and training for the support team, maintaining an effective parenteral nutrition order form or program, increasing collaboration among team members, creating and adhering to parenteral nutrition guidelines, and having parenteral nutrition rounds to regularly review parenteral nutrition orders. These approaches resulted in improved compliance with safe practice standards, improved percentage of patients with appropriate indications for total parenteral nutrition, adequate glycemic control, increased number of patients receiving parenteral nutrition within 10% of caloric need, and decreased time to full enteral feeds (additional cost savings) (14).

The goal of parenteral nutrition is to supply the optimal energy and nutrients that the patient would be achieving via the enteral route. Benefits of parenteral nutrition is more apparent in premature neonates, especially extremely low birthweight infants and very low birthweight infants. Previous approaches to formulate nutrition plans referenced the growth of similar-aged neonates to each other. Most premature infants experience extra-uterine growth restriction during their hospital course due to the inability to provide optimal nutrients and energy that matches in utero accretion. New strategies are being designed to mimic the growth occurring in the fetus of the same gestational age. Growth restriction is a significant problem as numerous studies have shown definitively that undernutrition, especially of protein, at critical stages of development produces long-term short stature, organ growth failure, neuronal deficits of number and dendritic connections, and later adverse behavioral and cognitive outcomes (43).

Adverse effects

Table 3. Complications of Total Parenteral Nutrition

Acute		Chronic
Metabolic complications		Systemic complications
	• Hypoglycemia • Hyperglycemia • Metabolic acidosis • Hypophosphatemia and other electrolytes imbalance • Hyperlipidemia		• Parenteral nutrition–associated liver disease • Metabolic bone disease
Mechanical complications		Infectious complications
	• Extravasation and tissue necrosis • Infiltration • Thrombosis • Pleural or pericardial effusion • Cardiac arrhythmia from malposition of catheter		• Bacterial infections especially staphylococcal species • Fungal infections: Candida species, Malassezia furfur

(77)

Glucose intolerance. Hyperglycemia is more common than hypoglycemia in infants receiving total parenteral nutrition. It is more pronounced in extremely low birth weight infants receiving high dextrose containing parenteral nutrition; however, early provision of well-balanced total parenteral nutrition with amino acid improves glucose tolerance (02). Studies have shown that the early introduction of parenteral amino acids has been shown to decrease the risk of hyperglycemia by stimulating endogenous insulin production (61). Hyperglycemia is often seen in sick patients, resulting from metabolic stress or a surge of counter regulatory hormones such as cortisol and norepinephrine. Steroids, infection, and respiratory distress can increase metabolic demand and create a catabolic state in which higher energy intake is needed, frequently leading to hyperglycemia. Hypoglycemia is not common while on parenteral nutrition, although hypoglycemia is recognized as a risk factor for morbidity, numerous studies have also shown that hyperglycemia in patients on parenteral nutrition correlates with increased hospital complications, as well as higher morbidity and mortality (60; 76).

Parenteral nutrition-associated liver disease (PNALD). Among the complications associated with long-term use of parenteral nutrition, the incidence of parenteral nutrition-associated liver disease (PNALD) ranges from 40% to 85% in infants. Histologic cholestatic changes in the liver can be observed within 2 weeks, and fibrosis is detected within 6 weeks of commencing parenteral nutrition. The use of parenteral nutrition in the neonatal intensive care unit is common with nearly 70% of patients in a 2007 study receiving parenteral nutrition at some point during hospitalization and 21% of patients receiving parenteral nutrition for greater than 21 days or more (26). PNALD may be diagnosed initially by abnormalities in laboratory findings, including increased liver enzymes and/or direct bilirubin concentrations. PNALD is defined as a concentration of direct bilirubin greater than 2 mg/dL on 2 consecutive measurements along with elevations in transaminases not associated with other known causes of cholestasis. Enteral feeding remains the best strategy to reverse and prevent parenteral nutrition-associated liver disease, with even 10% of caloric intake has shown beneficial effects (29). Patients whose direct bilirubin was 10 mg/dL or more had a nearly 40% chance of death or a liver transplant prior to modern practices of lipid reduction strategies and use of fish oil lipid emulsions (109).

The exact etiology of PNALD is not clear, but multiple risk factors have been identified: prematurity, low birth weight, small for gestational age, prolonged course of parenteral nutrition, intestinal starvation, catheter-related sepsis, photo-oxidation of parenteral nutrients, especially amino acids (10; 75), and the presence of surgical issues that preclude enteral nutrition for varied periods of time. Lack of enteral nutrition worsens hepatic disease secondary to reduced bile flow and decreased secretion of gastric hormones.

Studies have demonstrated that n-6 PUFA (represents > 60% of fatty acids in soy-based lipid emulsions) may favor the development of PNALD and promote increased pro-inflammatory mediators. In addition, soybean oil emulsions contain high levels of plant-based phytosterols, which correlate with severity of cholestasis (71). Because discontinuing lipid emulsions in neonates and children dependent on parenteral nutrition can result in essential fatty acid deficiency, poor growth, and poor neurodevelopmental outcome, new lipid emulsions have been developed.

Studies have shown that the dose and composition of intravenous fatty acid emulsions may play an important role in the development and progression of PNALD (23). In patients who develop PNALD while on soy or safflower oil emulsions, changing to fish oil emulsion reverses their PNALD (31). Fish oil-based emulsions, with a higher content in n-3 PUFA, have successfully been used in infants with PNALD as treatment and as nutritional support (40; 82). Multiple studies show fish oil-based emulsions are superior to mixed lipid emulsions in treating PNALD (69; 87), and mixed lipid emulsions seem to be useful in preventing PNALD associated with soybean oil lipid emulsions (78). Smoflipid^® has been shown to be safe and is associated with increased levels of docosahexaenoic acid and eicosapentaenoic acid, with conversely lower arachidonic acid levels in both erythrocyte membranes and plasma of premature infants as compared to pure soy emulsions. Smoflipid^® has also been found to have a positive effect in lowering total bilirubin, with the fish oil component associated with the reversal of PNALD in some infants (51; 69; 78; 34). Fish oil emulsion is prescribed at 1 g/kg/d. Studies have shown that when 1 g/kg/d of exclusive fish oil is substituted for soybean-based lipids, direct hyperbilirubinemia is more likely to resolve and incidence of death may be reduced (40; 22; 81).

Restriction of lipid emulsions may prevent the development of PNALD. Cycling parenteral nutrition with an “off” period each day, as opposed to continuous parenteral nutrition, can reduce the incidence of PNALD without associated calcium, phosphorus, magnesium, or vitamin D losses (93). However, cycling parenteral nutrition in infants younger than 6 months has not been well studied and is not recommended. The risk of PNALD can also be reduced by beginning enteral nutrition as soon as possible and by avoiding overfeeding. Decreasing fat emulsion infusion to 1 g/kg/day, based on the evidence that n-6 PUFA and phytosterols are hepatotoxic and pro-inflammatory (71), has proven not to be beneficial (72; 59). However, infants receiving lipid minimization at 1 gram/kg/day in contrast to 3 gram/kg/day had serum direct bilirubin levels rise at a slower rate than controls (23). More studies evaluating the role of lipid restriction are needed. Enteral feeding remains the best strategy to reverse and prevent PNALD, with as little as 10% of caloric intake showing beneficial effects (29; 75).

Metabolic bone disease. Metabolic bone disease, or osteopenia, is defined as a reduction in bone mineral content (osteopenia). It is a multifactorial disorder mainly seen in very low birth weight infants (premature infants less than 32 weeks’ gestation) from lack of fetal mineralization during the last trimester. The incidence is greater in extremely low birth weight infants. The incidence is inversely proportional to birth weight and gestational age of the infant and seen in 16% to 40% of very low birth weight infants and extremely low birth weight infants. The prevalence is higher in breast fed premature infants (40%) compared to preterm formula fed infants (16%) (95; 01). The clinical signs of metabolic bone disease in premature infants appear between 5 and 11 weeks of life and are characterized by an increased work of breathing due to chest wall instability caused by softening of ribs, an enlargement of the cranial sutures, rickets, fractures, and postnatal growth failure (37).

Osteopenia is more likely seen in premature patients not receiving enteral nutrition and most often manifests as hypophosphatemic metabolic bone disease progressing to rickets. Therefore, it is recommended to supply a calcium content of 75 to 90 mg/kg/day, a phosphorus content of 60 to 67 mg/kg/day, and a magnesium content of 7.5 to 10.5 mg/kg/day. This should correspond to a calcium to phosphorus ratio of 1.3:1 by weight and 1:1 by molar ratio in the parenteral solution. Traditionally, parenteral nutrition cannot provide the necessary amounts of calcium and phosphorus due to precipitation in the parenteral nutrition solutions; however, this is no longer a concern in countries that have organic phosphate preparations available (30).

It has been shown that early aggressive parenteral nutrition can impact calcium and phosphorus homeostasis, leading to hypophosphatemia and hypercalcemia. This result is most apparent with higher amino acid intake, namely greater than 2 g/kg/day (16). Because of this, in addition to a preterm infant’s inherent risk of osteopenia, the need for appropriate calcium to phosphorus ratio to combat hypophosphatemia is critical.

There are no specific methods for diagnosing metabolic bone disease. Often serum markers are used, including calcium, phosphate, alkaline phosphatase, parathyroid hormone, and vitamin D. Alkaline phosphatase levels higher than 900 IU/L in preterm infants younger than 33 weeks’ gestational age, associated with serum phosphate levels persistently lower than 5.6 mg/dL (< 1.8 mmol/L), have a diagnostic sensitivity and specificity of 70% and 100%, respectively, for metabolic bone disease of prematurity (37). Commonly used imaging study is the x-ray of long bones and ribs. Osteopenia may be diagnosed on x-ray based on evidence of reduced bone mineral density. Dual energy x-ray absorptiometry is the gold standard technique to assess bone mineral density. Backström and colleagues found that the association of alkaline phosphatase serum levels more than 900 IU/L and phosphate less than 1.8 mmol/L indicates a low bone mineral density with a sensitivity and specificity of 100% and 70%, respectively, compared to dual-energy x-ray absorptiometry measurements in very low birth weight and extremely low birth weight infants younger than 33 weeks’ gestation and a mean birth weight of 1490 g (06).

Although there are no standard recommendations on screening for metabolic bone disease in premature infants, high index of suspicion with abnormal labs warrants further investigations and treatment (41). Hypophosphatemic rickets in these infants respond well to increased phosphate supplement in total parenteral calories and minerals, especially calcium and phosphorus. This form of osteopathy does not respond to vitamin D nutrition or as a dietary supplement. Premature infants receiving breast milk should have appropriate fortification to enhance therapy unless a deficiency is present. Also, ensure appropriate vitamin D store by providing 400 IU of vitamin D. The AAP recommends that all breast-fed, partially breast-fed and non-breast fed infants consuming less than 1000 IU of vitamin D fortified milk daily should be supplemented daily with a minimum of 400 IU vitamin D (108).

Infectious. Catheter-related blood stream infection is (CLABSI) potentially life threatening and occurs in 2% to 20% of patients receiving parenteral nutrition with highest rate being in extreme premature infant population. CLABSI is defined as a positive blood culture not related to another site of infection in a symptomatic patient with a central venous line in place at the time of or removed within 2 days prior to the onset of infection (24). In the United States, the CLABSI rate in intensive care units is estimated to be 0.8 per 1000 central line days. These complications can be prevented by aseptic line insertion and careful maintenance, such as sterile changing of infusion solutions, minimizing access to the line, and removing the catheters when it is no longer necessary. Adherence to insertion and maintenance bundles and use of checklists have been demonstrated to decrease catheter-related blood stream infection rates in NICUs in multiple studies (88). The Centers for Disease Control and Prevention recommends development and implementation of “bundles” to improve compliance and outcomes (73). Studies have demonstrated that implementing strategies that involve line site care, training for staff and parents, multidisciplinary discharge planning, and monitoring compliance reduce the rates of catheter-related blood stream infections (70). However, strict adherence to unit specific policies for prevention of central line associated blood stream infection is of paramount importance, as high compliance with a checklist for insertion and daily line necessity is significantly associated with lower catheter-related blood stream rate. Long catheter stay is one of the risk factors for CLABSI. The incidence rate of CLABSI increased by 14% per day during the first 18 days after peripherally inserted central catheter (89). A central catheter should be removed as soon as possible once it is no longer necessary.

Current observations have indicated that use of mixed lipid emulsions have been associated with up to 25% decreased incidence of sepsis in very low birth weight infants compared to those receiving soybean lipid emulsions. More randomized controlled trial studies are still needed (106).

The disease process for which the patient is on parenteral nutrition, the coexisting disease processes, or adverse events of parenteral nutrition may increase the risk of morbidity or mortality. Now that infants are surviving longer on parenteral nutrition, new aspects must be explored concerning optimizing components, maximizing appropriate growth, mediating immune and inflammatory responses, and improving neurodevelopmental outcomes.

Scientific basis

Providing adequate volume, energy, and nutrients is important to promote an anabolic state while avoiding overfeeding. Energy and nutrient requirement are based on the sum of total losses (fecal, urinary, and dermal), catabolism, and nutrients required for growth. In most instances, parenteral nutrition requires less energy than enteral nutrition because parenteral nutrition provides better bioavailability of the nutrients and does not require energy expenditure for absorption and digestion. For example, in infants less than 10 kg, requirements have been shown to be 89 to 109 kcal/kg/day parenterally, whereas enteral requirements would be 105 to 128 kcal/kg/day. Negative energy balance has been correlated with increasing number of complications, particularly infections. Volume requirements will vary based on age and size of the patient, but volume per kilogram will decrease as the patient grows.