Parenteral nutrition in infants and children

Ian Griffin MD

General Child Neurology

Updated 03.29.2024
Released 07.25.2003
Expires For CME 03.29.2027

Parenteral nutrition in infants and children

Author: Ian Griffin MD

See Contributor Disclosures

Editor: Bernard L Maria MD

Parenteral nutrition in infants and children

In This Article

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Introduction

Overview

In this article, the authors discuss the risks and benefits of parenteral nutrition in infants and children, specific nutritional requirements, and the management of infants and children receiving parenteral nutrition.

Key points

	• The goal of optimal nutrition in the newborn period for premature infants, especially very low birth weight infants, is to make intrauterine growth rate.
	• Parenteral nutrition is a useful bridge until adequate nutrition can be achieved by the preferred enteral route.
	• In acutely ill-term infants and children, the duration of parenteral nutrition may be shorter, and the risk-benefit calculation more nuanced, than in extremely preterm infants.
	• A multidisciplinary team approach is crucial in providing optimal and safe parenteral nutrition while decreasing time to full enteral feeds and preventing central line-associated bloodstream infection.

Historical note and terminology

Parenteral nutrition entails providing nutrients via an intravenous route when some or all nutrition cannot be provided via the intestinal tract. Total parenteral nutrition consists of water, dextrose, amino acids, intravenous lipid emulsions, and micro- and macronutrients. In most preterm infants, parenteral nutrition should be considered a brief, time-limited intervention until adequate enteral can be achieved. Longer-term use of parenteral nutrition significantly increases the risks of the intervention.

Clinical aspects

Description

Parenteral nutrition implies the administration of a balanced, all-inclusive mixture of nutrients, including carbohydrates (glucose), protein (amino acid), lipids, and macro- and micro-minerals. Total parenteral nutrition implies the absence of any other source of nutrition, for example, by the enteral route. Partial parenteral nutrition refers to the instance where parenteral nutrition provides a supplement to enteral nutrition.

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 (14). Hyperglycemia and hypoglycemia are common complications in preterm infants, but the management of blood glucose remains extremely controversial. Although it is clear that low blood glucose is detrimental in the short and medium term, the exact threshold for harm (or even if there is a threshold) is unknown (110). Conversely, there are multiple theoretical concerns about high blood glucose levels. Once again, however, the threshold for harm is undefined. Some authors have suggested that glucose more than 150 mg/dL should be considered hyperglycemia (98), but this would likely expose many preterm infants to insulin treatment (thus, the risk of hypoglycemia) for uncertain benefit. Blood glucose levels greater than 360 mg/dL may cause significant osmolar changes resulting in dehydration and electrolyte derangements, and they are statistically associated with an increased risk of cerebral damage, necrotizing enterocolitis, retinopathy of prematurity, and intraventricular hemorrhage (42; 49; 03); however, whether they are simply associations, or whether they are causes or effects of hyperglycemia, is not clear.

In the Swedish EXPRESS study of infants born at least 27 weeks gestational age, the incidence of hyperglycemia (> 180 mg/dL) was approximately 30%, but a 1 g/kg/d increase in glucose infusion rate was only associated with a 1.6% increase in the rate of hypoglycemia (120). There are concerns about the effects of the main tools to reduce hyperglycemia, including insulin administration and reduction in glucose intake (and the resulting reduced calorie intake and possible effects on early growth) (87). The use of insulin infusions to prevent or reduce hyperglycemia has been shown to result in a modest reduction in hyperglycemia but at the cost of an increased frequency and severity of hypoglycemia (17). In another study, very low birth weight infants who were defined as hyperglycemic (2 measurements more than 4 hours apart > 153 mg/dl) to target a blood sugar between 72 and 108 mg/dL or between 144 and 180 mg/dL showed little differences in outcomes (04). Tighter glucose control was associated with more rapid weight and head circumference gains but with reduced linear growth and an increased rate of hypoglycemia (04). Pragmatically, the safest approach in treating hyperglycemia is to lower the glucose infusion rate rather than add insulin due to its associated risks (63).

Guidelines from ESPGHAN suggest that parenteral glucose delivery to preterm infants should begin at 2 to 4 mg/kg/min (2.9 to 5.8 g/kg/d) and increase to 8 to 10 mg/kg/min (11.5 to 14.4 g/kg/d), although many, including the current author and the National Institute for Clinical Evidence in the United Kingdom, would consider these amounts too low, especially the starting intake where a value of 6 to 9 g/kg/d would seem more appropriate (75). In term infants, ESPGHAN suggests starting at 2.5 to 5.0 mg/kg/min (3.6 to 7.2 g/kg/d) and increasing to 5 to 10 mg/kg/min (7.2 to 14.4 g/kg/d) (64). In infants aged older than 28 days, infusion rates would be lower and would steadily increase from the acute phase of the illness to the stable phase and then to the recovery phase; they would be higher (as g/kg/d) in smaller infants (64).

In the PICU, blood glucose levels above 145 mg/dL should be avoided (64). ESPGHAN also recommends that blood glucose above 145 mg/dL be avoided in the NICU, and recurrent levels above 180 mg/dL should be treated with insulin if reductions in glucose infusion have been inadequate to control blood glucose (64). Once again, some, including the current author, would consider these treatment levels too aggressive.

Unfortunately, despite the importance of blood glucose control, the real definition of what plasma glucose is too low or too high is unknown and may be an inadequate question (perhaps being affected by clinical state, metabolic demands, developmental stage, and the availability of other substrates). Similarly, the balance of risks and benefits of insulin treatment of hyperglycemia in preterm neonates remains unclear (08; 04).

Protein. The primary 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 protein loss (in urine, feces, skin cells, and secretions) is about 1 g/kg per day if no supplemental protein is given (30). The estimated daily protein accretion of a fetus at about 28 weeks of gestation is 2 g/kg/day; at least 3 to 3.5 g/kg/day of amino acids is needed to promote protein accretion while allowing for obligatory losses (121). 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/kg/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 (109).

Studies support that providing 2 to 3.5 g/kg per day of amino acid shortly after birth is well tolerated and improves protein accretion (102; 47; 100; 44). There are now more data to support even higher intakes of up to 4 g/kg/day during the first week (25; 69). Traditionally, 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 (10). Contradictory data on developmental outcomes have been reported; Bayley Mental Developmental Index scores were lower with the high amino acid intake at 12 months but improved by 24 months (11). Weight, height, and head circumference were lower than in infants with standard amino acid intakes. Most studies have shown no 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) (84; 100; 48; 10; 18; 105).

Administering a high dose (more than 3 g/kg/day) or an early dose (less than 24hrs) of parenteral amino acid is safe and well tolerated but does not offer significant benefits with regard to growth (58). ESPGHAN guidelines for preterm infants recommend that parenteral amino acid intakes above 3.5 g/kg/d should only be administered as a part of clinical trials (56). In contrast, evidence-based guidelines from the United Kingdom suggest that intakes up to 4 g/kg/d are reasonable after the first few days of life in preterm infants (75).

Evidence suggests that there may be advantages to somewhat lower amino acids in infants (2.5 to 3.0 g/kg/day) in the first week of life. Bloomfield and colleagues randomized 434 extremely preterm infants to receive an additional 1g/day of parenteral amino acids or placebo (12). Although the primary outcome (survival free of neurodevelopmental impairment at 2 years) was not different between groups, moderate to severe neurodevelopmental impairment at 2 years was more common in the infants who received the higher amino acid intake (relative risk, 1.95; 95% CI, 1.09 to 3.48).

Special attention should be paid to calcium and phosphorus levels in preterm infants who receive a high amino acid infusion during the first week of life. 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 three 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 (17).

Emphasis should be placed on providing optimal protein and energy during the first week of life in preterm infants (95) and transitioning to enteral feeds as quickly as safely possible. 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 (95) and a lower likelihood of length growth restriction. In fact, early administration of amino acids improves the weight of preterm infants (107), decreases postnatal growth restriction (25), and improves postnatal head growth (69). 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 (82). Van den Akker and colleagues found no difference in growth, but they did find 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 (108). 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 (77). 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 (07).

Despite the increase in protein nutrition, parenteral nutrition-dependent very premature infants are still at risk of deficiency for the conditionally essential amino acids, particularly tyrosine, glutamine, cysteine, and arginine (101). Even with supplementation to traditional amino acid solutions using a standardized, concentrated, added macronutrient parenteral (SCAMP) nutrition regimen, very premature infants did not achieve conditionally essential amino acid levels that reached reference ranges (68). 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).

Lipids and essential fatty acids. Lipids are iso-osmolar and provide more calories per 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 amounts 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 (06). There is no evidence that gradual increments in the rate of infusion of lipids improve fat tolerance; however, higher amounts of lipids (2 to 3 g/kg/d) on the first day of life may result in hyperlipidemia (115). 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 the lowest possible rate (0.25 g/kg/d) to prevent essential fatty acid deficiency.

Evidence shows that early introduction of parenteral lipids during the first week is safe and well tolerated in very low birth weight infants (114; 56). It is also associated with weight gain and could improve early nutritional support for these preterm neonates (39).

Soybean emulsions contain a high ratio of omega-6 to omega-3 fatty acids, which, in turn, leads to lesser proportions of omega-3 fatty acid derivatives, docosahexaenoic acid and eicosapentaenoic acid. Both docosahexaenoic acid and eicosapentaenoic acid are important substances of neural and retinal development with anti-inflammatory properties (94). 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 (89). 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 lower phytosterols (104).

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, a 3-in-1 total nutrition formula was more manageable and easier to administer (24). It was also more cost-effective and required 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 using 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 omega-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; 90). 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 (88; 115). 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 (35). Evidence also demonstrates a reversal of established hepatic dysfunction (55; 81), but there was no prevention (38). There are three 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 (88; 81). 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 (31). 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 (22).

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). Micronutrients such as zinc, copper, selenium, and iodine should be added to parenteral nutrition in infants with very low birth weight within a few days after birth. Parenteral supplementation of iron, manganese, chromium, and molybdenum is rarely needed in infants with very low birth weight 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 the enteral route (34).

Trace elements are necessary for 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 months
20
2
0.20
1
0.25
1

50(5000) 100 ≥ 3 months
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.

The available concentrations of molybdenum and manganese are such that dilution of the manufacturer’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 (65)

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 allows.

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 (106). 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 (103). 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 been shown to improve nitrogen balance and extrauterine 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 an unstable medical condition.

Contraindications

Parenteral nutrition is contraindicated in patients with functioning bowels 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 in optimizing parenteral nutrition, maintaining accuracy of the parenteral nutrition delivered, decreasing adverse effects, and improving outcomes 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 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 review parenteral nutrition orders regularly. 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) (13).

The goal of parenteral nutrition is to supply the optimal energy and nutrients that the patient would be achieving via the enteral route The benefits of parenteral nutrition are more apparent in premature neonates, especially extremely low birthweight infants and very low birthweight infants. Previous approaches to formulating 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 match in-utero accretion. 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 electrolyte 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
(80)

Good evidence-based guidelines are available for managing parenteral nutrition complications, specifically those related to the need for a central venous line (118).

Glucose intolerance. Hyperglycemia is more common than hypoglycemia in infants receiving total parenteral nutrition. It is more pronounced in extremely low birth weight infants, although glucose infusion rate has a statistically significant but clinically small effect (120). Early provision of well-balanced total parenteral nutrition with amino acids improves glucose tolerance (02). Studies have shown that the early introduction of parenteral amino acids decreases the risk of hyperglycemia by stimulating endogenous insulin production (61). In sick patients, hyperglycemia often results 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; 79).

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 (23). PNALD may be diagnosed initially by abnormalities in laboratory findings, including increased liver enzymes or direct bilirubin concentrations. PNALD is defined as a concentration of direct bilirubin greater than 2 mg/dL on two 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 showing beneficial effects (26). Patients whose direct bilirubin was 10 mg/dL or more had a nearly 40% chance of death or a liver transplant before modern practices of lipid reduction strategies and the use of fish oil lipid emulsions (119).

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 (09; 78), and the presence of surgical issues that preclude enteral nutrition for varied periods of time.

Studies have demonstrated that n-6 PUFA (representing greater than 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 the severity of cholestasis (73). Because discontinuing lipid emulsions in neonates and children dependent on parenteral nutrition can result in essential fatty acid deficiency, poor growth, and poor neurodevelopmental outcomes, 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 (20). In patients who develop PNALD while on soy or safflower oil emulsions, changing to fish oil emulsion reverses their PNALD (29). Fish oil-based emulsions, with a higher content in n-3 PUFA, have successfully been used in infants with PNALD as treatment and nutritional support (40; 86). Multiple studies show fish oil-based emulsions are superior to mixed lipid emulsions in treating PNALD (71; 91), and mixed lipid emulsions seem to be useful in preventing PNALD associated with soybean oil lipid emulsions (81). 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; 71; 81; 32). 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; 19; 85).

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 (96). 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 (73), has proven not to be beneficial (74; 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 (20). 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 (26; 78).

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 is seen in 16% to 40% of infants with very low or extremely low birth weight. The prevalence is higher in breast-fed premature infants (40%) compared to preterm formula-fed infants (16%) (99; 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 (36).

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 with organic phosphate preparations available (28).

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 more than 2 g/kg/day (16). Because of this, in addition to a preterm infant’s inherent risk of osteopenia, the need for an 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 (36). A 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 higher 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 infants with very low and extremely low birth weight who are younger than 33 weeks gestation and have a mean birth weight of 1490 g (05).

Although there are no standard recommendations on screening for metabolic bone disease in premature infants, a high index of suspicion with abnormal labs warrants further investigations and treatment (41). Hypophosphatemic rickets in these infants respond well to increased phosphate supplementation 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 storage 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 (116).

Infectious. Catheter-related bloodstream infection is (CLABSI) potentially life-threatening and occurs in 2% to 20% of patients receiving parenteral nutrition, with the highest rate being in the extremely 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 before the onset of infection (21). 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. In multiple studies, adherence to insertion and maintenance bundles and the use of checklists have been demonstrated to decrease catheter-related bloodstream infection rates in NICUs (92). The Centers for Disease Control and Prevention recommends development and implementation of “bundles” to improve compliance and outcomes (76). 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 bloodstream infections (72). However, strict adherence to unit-specific policies for the prevention of central line-associated bloodstream infection is of paramount importance, as high compliance with a checklist for insertion and daily line necessity is significantly associated with lower catheter-related bloodstream 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 (93). A central catheter should be removed as soon as possible once it is no longer necessary.

Observations have indicated that use of mixed lipid emulsions has 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 (114).

In older children, especially those needing prolonged parenteral nutrition and prolonged central venous access, newer modalities that may be helpful in the prevention or treatment of CLABSI include using ethanol locks and taurolidine citrate locks (118).

Others. Other complications of parenteral nutrition include hyperlipidemia, hypercalcemia, and electrolyte abnormalities. The risks of these can be reduced by careful prescribing and close monitoring. There is also the risk of inadvertent contamination of the parenteral nutrition solutions with exogenous toxic compounds, for example, aluminum (83) and manganese (37; 33). Parenteral nutrition is a common source of medical errors (27), which may be reduced by using a limited number of standardized parenteral nutrition formulations (15).

Special considerations

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

	• Despite being a common cause of medical error, objective evidence in favor of parenteral nutrition (rather than dextrose/ electrolyte solutions) from randomized controlled trials is limited.
	• Parenteral nutrition may be required in preterm infants to approximate the in-utero accretion rates of nutrients as enteral feeds are advanced, and there is a strong physiological argument in favor of parenteral nutrition, especially its establishment/advancement of enteral feeds is slow or delayed.
	• It is possible that as enteral feeds are advanced more rapidly in preterm infants, the relative benefits of parenteral nutrition may be reduced, especially in larger infants in whom full enteral feeds can be established much more quickly.

More than 750,000 orders for parenteral nutrition are made in U.S. NICU annually, and parenteral nutrition remains a common cause of medical errors (27). In preterm infants, the earlier administration of parenteral nutrition or the addition of intravenous amino acids to dextrose/electrolyte solutions (typically within the first day rather than at the end of the first week) has been shown to provide short-term growth benefits (70; 97) and improve early nitrogen balance (105). In one observational population-based study, it may also increase survival, albeit at the cost of increased morbidity; however, such studies are subject to the effect of unidentified confounding variables (117).

The evidence is less clear for term neonates, especially those requiring relatively brief periods of parenteral nutrition. In one study of term-born infants admitted to the PICU (a subgroup analysis of the PEPaNIC study), later introduction of parenteral nutrition (towards the end of the first week of life) compared to earlier introduction was associated with benefits in terms of reduced infections and earlier PICU discharge (112), but the quality of evidence in this population is generally poor (113; 67).

The main PEPaNIC study compared the late introduction of parenteral nutrition (towards the end of the first week of life) to earlier introduction of parenteral nutrition in infants and children admitted to the PICU (111), including those much older than the previously reported subgroup analysis of term infants (112). Although early weight loss was associated with worse outcomes, this did not differ between the "early" and "late" parenteral nutrition groups (111). Later introduction of parenteral nutrition was associated with significant cost savings, which exceeded the amount expected simply from the nonprescription of parenteral nutrition (112; 111). At the 2-year follow-up, there were no differences in survival, growth, neurodevelopmental outcome, or health-related quality of life, but some developmental subdomains (such as executive functioning and working memory) were improved in the group with delayed introduction of parenteral nutrition (113; 46). The subgroup of infants who were undernourished at admission did worse than well-nourished infants, but even in this group, delayed introduction of parenteral nutrition did not affect early weight loss or mortality, but there were, however, significantly fewer line infections and earlier discharge from the PICU (112; 111).

References

01: Abrams SA. In utero physiology: role in nutrient delivery and fetal development for calcium, phosphorus, and vitamin D. Am J Clin Nutr 2007;85(2):604S-7S. PMID 17284763
02: Adamkin H. Nutrition management of the very low-birth weight infant. NeoReviews 2006;7(12):e602-7. PMID 24873840
03: Alexandrou G, Skiöld B, Karlén J, et al. Early hyperglycemia is a risk factor for death and white matter reduction in preterm infants. Pediatrics 2010;125(3):e584-91. PMID 20176674
04: Alsweiler JM, Harding JE, Bloomfield FH. Tight glycemic control with insulin in hyperglycemic preterm babies: a randomized controlled trial. Pediatrics 2012;129(4):639-47. PMID 22430450
05: Backström MC, Kouri T, Kuusela AL, et al. Bone isoenzyme of serum alkaline phosphatase and serum inorganic phosphate in metabolic bone disease of prematurity. Acta Paediatr 2000;89(7):867-73. PMID 10943972
06: Baisden B, Bunyapen C, Bhatia J. Feeding the Premature Infant. In: Berdanier CD, Dwyer, J, Beldman EB, editors. Handbook of Nutrition and Food. 2nd ed. Boca Raton, FL: CRC Press, 2008:259-70.
07: Balakrishnan M, Jennings A, Przystac L, et al. Growth and neurodevelopmental outcomes of early, high-dose parenteral amino acid intake in very low birth weight infants: a randomized controlled trial. JPEN J Parenter Enteral Nutr 2018;42(3):597-606. PMID 29187120
08: Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Early insulin therapy in very-low-birth-weight infants. N Engl J Med 2008;359(18):1873-84. PMID 18971490
09: Bhatia J, Moslen MT, Haque AK, Mccleery R, Rassin DK. Total parenteral nutrition-associated alterations in hepatobiliary function and histology in rats: is light exposure a clue? Pediatr Res 1993;33(5):487-92. PMID 8511021
10: Blanco CL, Falck A, Green BK, Cornell JE, Gong AK. Metabolic responses to early and high protein supplementation in a randomized trial evaluating the prevention of hyperkalemia in extremely low birth weight infants. J Pediatr 2008;153(4):535-40. PMID 18589451
11: Blanco CL, Gong AK, Schoolfield J, et al. Impact of early and high amino acid supplementation on ELBW infants at 2 years. J Pediatr Gastroenterol Nutr 2012;54(5):601-7. PMID 22228000
12: Bloomfield FH, Jiang Y, Harding JE, Crowther CA, Cormack BE, ProVIDe Trial Group. early amino acids in extremely preterm infants and neurodisability at 2 years. N Engl J Med 2022;387(18):1661. PMID 36322845
13: Boitano M, Bojak S, McCloskey S, McCaul DS, McDonough M. Improving the safety and effectiveness of parenteral nutrition: results of a quality improvement collaboration. Nutr Clin Pract 2010;25(6):663-71. PMID 21139133
14: Bolder U, Ebener C, Hauner H, et al. Carbohydrates—Guidelines on parenteral nutrition, chapter 5. Ger Med Sci 2009;7:Doc23. PMID 20049080
15: Bolisetty S, Pharande P, Nirthanakumaran L, et al. Improved nutrient intake following implementation of the consensus standardised parenteral nutrition formulations in preterm neonates--a before-after intervention study. BMC Pediatr 2014;14:309. PMID 25514973
16: Bonsante F, Iacobelli S, Latorre G, et al. Initial amino acid intake influences phosphorus and calcium homeostasis in preterm infants--it is time to change the composition of the early parenteral nutrition. PLoS ONE 2013;8(8):e72880. PMID 23977367
17: Bottino M, Cowett RM, Sinclair JC. Interventions for treatment of neonatal hyperglycemia in very low birth weight infants. Cochrane Database Syst Rev 2011;10:CD007453. PMID 21975769
18: Bulbul A, Okan F, Bulbul F, Nuhoglu A. Effect of low versus high early parenteral nutrition on plasma amino acid profiles in very low birth-weight infants. J Matern Fetal Neonatal Med 2012;25(6):770-6. PMID 21770835
19: Calkins KL, Dunn JC, Shew SB, et al. Pediatric intestinal failure–associated liver disease is reversed with 6 months of intravenous fish oil. JPEN J Parenter Enteral Nutr 2014;28(6):682-92. PMID 23894176
20: Calkins KL, Havranek T, Kelley-Quon LI, et al. Low-dose parenteral soybean oil for the prevention of parenteral nutrition-associated liver disease in neonates with gastrointestinal disorders. JPEN J Parenter Enteral Nutr 2017;41(3):404-11. PMID 26024828
21: Centers for Disease Control and Prevention. Bloodstream infection event (central line associated blood stream infection and non-central line-associated bloodstream infection). Available at: http://www.cdc.gov/nhsn/PDFs/pscManual/4PSC_CLABScurrent.pdf. Accessed June 2018.
22: Choudhary N, Tan K, Malhotra A. Inpatient outcomes of preterm infants receiving w-3 enriched lipid emulsion (SMOFlipid): an observational study. Eur J Pediatr 2018;177(5):723-31. PMID 29445923
23: Christensen RD, Henry E, Wiedmeier SE, Burnett J, Lambert DK. Identifying patients, on the first day of life, at high-risk of developing parenteral nutrition-associated liver disease. J Perinatol 2007;27(5):284-90. PMID 17344923
24: Colomb V, Marlowe ML, Monnot D, Rigo J. Practical use of a new three-chamber bag for parenteral nutrition in pediatric patients. e-SPEN Journal 2012;7:e93-9.
25: Cormack BE, Bloomfield FH. Increased protein intake decreases postnatal growth faltering in ELBW babies. Arch Dis Child Fetal Neonatal Ed 2013;98(5):F399-404. PMID 23487551
26: Costa S, Maggio L, Sindico P, Cota F, De Carolis MP, Romagnoli C. Preterm small for gestational age infants are not higher risk for parenteral nutrition-associated cholestasis. J Pediatr 2010;156(4):575-9. PMID 20036379
27: Costakos DT. Of lobsters, electronic medical records, and neonatal total parenteral nutrition. Pediatrics 2006;117(2):e328-32. PMID 16452339
28: De Curtis M, Rigo J. The nutrition of preterm infants. Early Hum Dev 2012;88 Suppl 1:S5-7. PMID 22261289
29: de Meijer VE, Gura KM, Meisel JA, Le HD, Puder M. Parenteral fish oil monotherapy in the management of patients with parenteral nutrition-associated liver disease. Arch Surg 2010;145(6):547-51. PMID 20566974
30: Denne SC. Protein and energy requirements in preterm infants. Semin Neonatol 2001;6(5):377-82. PMID 11988027
31: Deshpande G, Simmer K, Deshmukh M, Mori TA, Croft KD, Kristensen J. Fish oil (SMOFlipid) and olive oil lipid (Clinoleic) in very preterm neonates. J Pediatr Gastroenterol Nutr 2014;58(2):177-82. PMID 24048161
32: Diamond IR, Grant RC, Pencharz PB, et al. Preventing the progression of intestinal failure–associated liver disease in infants using a composite lipid emulsion: a pilot randomized controlled trial of SMOFlipid. JPEN J Parenter Enteral Nutr 2017;41(5):866-77. PMID 26838529
33: Dickerson RN. Manganese intoxication and parenteral nutrition. Nutrition 2001;17(7-8):689-93. PMID 11448607
34: Domellof M. Nutritional care of premature infants: microminerals. World Rev Nutr Diet 2014;110:121-39. PMID 24751625
35: Ernst KD. Essential fatty acid deficiency during parenteral soybean oil lipid minimization. J Perinatol 2017;37(6):695-7. PMID 28333161
36: Faienza M, D’Amato E, Natale M, et al. Metabolic bone disease of prematurity: diagnosis and management. Front Pediatr 2019;7:143. PMID 31032241
37: Fell JM, Reynolds AP, Meadows N, et al. Manganese toxicity in children receiving long-term parenteral nutrition. Lancet 1996;347(9010):1218-21. PMID 8622451
38: Finn KL, Chung M, Rothpletz-Puglia P, Byham-Gray L. Impact of providing a combination lipid emulsion compared with a standard soybean oil lipid emulsion in children receiving parenteral nutrition: a systematic review and meta-analysis. JPEN J Parenter Enteral Nutr 2015;39(6):656-67. PMID 25057053
39: Fischer CJ, Maurcort-Boulch D, Essomo Megnier-Mbo CM, Remontet L, Claris O. Early parenteral lipids and growth velocity in extremely low birth weight infants. Clin Nutr 2014;33(3):502-8. PMID 23958274
40: Gura KM, Lee S, Valim C, et al. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics 2008;121(3):e678-86. PMID 18310188
41: Harrison CM, Johnson K, McKechnie E. Osteopenia of prematurity: a national review of practice. Acta Paediatr 2008;(4):407-13. PMID 18363949
42: Hawdon JM. Disorders of blood glucose homeostasis in the neonate. In: Rennie JM, Roberton NRC, eds. Roberton’s Textbook of Neonatology. 4th edition. London, United Kingdom: Elsevier Churchill Livingstone, 2005:862-5.
43: Hay WW Jr. Strategies for feeding the preterm infant. Neonatology 2008;94(4):245-54. PMID 18836284
44: Hay WW, Thureen P. Protein for preterm infants: how much is needed? How much is enough? How much is too much? Pediatr Neonatology 2010; 51(4):198-207. PMID 20713283
45: Hermsen JL, Sano Y, Kudsk KA. Food fight! Parenteral nutrition, enteral stimulation and gut-derived mucosal immunity. Langenbecks Arch Surg 2009;394(1):17-30. PMID 18521625
46: Hordijk J, Verbruggen S, Vanhorebeek I, et al. Health-related quality of life of children and their parents 2 years after critical illness: pre-planned follow-up of the PEPaNIC international, randomized, controlled trial. Crit Care 2020;24(1):347. PMID 32546247
47: Ibrahim HM, Jeroudi MA, Baier RJ, Dhanireddy R, Krouskop RW. Aggressive early total parenteral nutrition in low-birth-weight infants. J Perinatol 2004;24(8):482-6. PMID 15167885
48: Jadhav P, Parimi PS, Kalhan SC. Parenteral amino acid and metabolic acidosis in premature infants. JPEN J Parenter Enteral Nutr 2007;31(4):278-83. PMID 17595435
49: Kao LS, Morris BH, Lally KP, Stewart CD, Huseby V, Kennedy KA. Hyperglycemia and morbidity and mortality in extremely low birth weight infants. J Perinatol 2006;26(12):730-6. PMID 16929344
50: Kapoor V, Glover R, Malviya MN. Alternative lipid emulsions versus pure soy oil based lipid emulsions for parenterally fed preterm infants. Cochrane Database Syst Rev 2015;(12):CD009172. PMID 26630252
51: Kelly DA. Preventing parenteral nutrition liver disease. Early Hum Dev 2010;86(11):683-7. PMID 20923719
52: Kleinman RE. Pediatric Nutrition Handbook. 7th Edition. Kleinman RE, editor. American Academy of Pediatrics, 2013:86-90.
53: Klek S. Omega-3 fatty acids in modern parenteral nutrition: a review of the current evidence. J Clin Med 2016;5(3). PMID 26959070
54: Koletzko B, Goulet O, Hunt J, et al. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr 2005;41 Suppl 2:S1-87. PMID 16254497
55: Lam HS, Tam YH, Poon TC, et al. A double-blind randomised controlled trial of fish oil-based versus soy-based lipid preparations in the treatment of infants with parenteral nutrition-associated cholestasis. Neonatology 2014;105(4):290-6. PMID 24576844
56: Lapillonne A, Fidler Mis N, Goulet O, et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: lipids. Clin Nutr 2018;37(6 Pt B):2324-36. PMID 30143306
57: Le HD, Fallon EM, de Meijer VE, Malkan AD, Puder M, Gura KM. Innovative parenteral and enteral nutritional therapy for intestinal failure. Semin Pediatr Surg 2010;19(1):27-34. PMID 20123271
58: Leenders EKSM, de Waard M, van Goudoever JB. Low- versus high-dose and early versus late parenteral amino-acid administration in very-low-birth-weight infants: a systematic review and meta-Analysis. Neonatology 2018;113(3):187-205. PMID 29268262
59: Levit OL, Calkins KL, Gibson LC, et al. Low-dose intravenous soybean oil emulsion for prevention of cholestasis in preterm neonates. JPEN J Parenter Enteral Nutr 2016;40(3):374-82. PMID 24963025
60: Lin LY, Lin HC, Lee PC, Ma WY, Lin HD. Hyperglycemia correlates with outcomes in patients receiving total parenteral nutrition. Am J Med Sci 2007;333(5):261-5. PMID 17505165
61: Mahaveer A, Grime C, Morgan C. Increasing early protein intake is associated with a reduction in insulin-treated hyperglycemia in very preterm infants. Nutr Clin Pract 2012;27(3):399-405. PMID 22516941
62: Martin CR, Dasilva DA, Cluette-Brown JE, et al. Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities. J Pediatr 2011;159(5):743-9. PMID 21658712
63: Meetze W, Bowsher R, Compton J, Moorehead H. Hyperglycemia in extremely- low-birth-weight infants. Biol Neonate 1998;74(3):214-21. PMID 9691162
64: Mesotten D, Joosten K, van Kempen A, Verbruggen S. ESPGHAN/ ESPEN/ ESPR/ CSPEN guidelines on pediatric parenteral nutrition: Carbohydrates. Clin Nutr 2018;37(6 Pt B):2337-43. PMID 30037708
65: Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutrition. JPEN J Parenter Enteral Nutr 2004;28(6):S39-70. PMID 15568296
66: Moe-Byrne T, Brown JV, McGuire W. Glutamine supplementation to prevent morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2016;4:CD001457. PMID 27089158
67: Moon K, Athalye-Jape GK, Rao U, Rao SC. Early versus late parenteral nutrition for critically ill term and late preterm infants. Cochrane Database Syst Rev 2020;4(4):CD013141. PMID 32266712
68: Morgan C, Burgess L. High protein intake does not prevent low plasma levels of conditionally essential amino acids in very preterm infants receiving parenteral nutrition. JPEN J Parenter Enteral Nutr 2017;41(3):455-62. PMID 26150412
69: Morgan C, McGowan P, Herwitker S, Hart AE, Turner MA. Postnatal head growth in preterm infants: a randomized controlled parenteral nutrition study. Pediatrics 2014;133(1):e120-8. PMID 24379229
70: Moyses HE, Johnson MJ, Leaf AA, Cornelius VR. Early parenteral nutrition and growth outcomes in preterm infants: a systematic review and meta-analysis. Am J Clin Nutr 2013;97(4):816-26. PMID 23446896
71: Muhammed R, Bremner R, Protheroe S, Johnson T, Holden C, Murphy MS. Resolution of parenteral nutrition-associated jaundice on changing from a soybean oil emulsion to a complex mixed-lipid emulsion. J. Pediatr Gastroenterol Nutr 2012;54(6):797-802. PMID 22157927
72: Muir A, Holden C, Sexton E, Gray JW. Preventing bloodstream infection in patients receiving home parenteral nutrition. J Pediatr Gastroenterol Nutr 2014;59(2):177-81. PMID 24796804
73: Nandivada P, Cowan E, Carlson SJ, Chang M, Gura KM, Puder M. Mechanisms for the effects of fish oil lipid emulsions in the management of parenteral nutrition-associated liver disease. Prostaglandins Leukot Essent Fatty Acids 2013;89(4):153-8. PMID 23602846
74: Nehra D, Fallon EM, Carlson SJ, et al. Provision of a soy-based intravenous lipid emulsion at 1 g/kg/d does not prevent cholestasis in neonates. JPEN J Parenter Enteral Nutr 2013;37(4):498-505. PMID 22767698
75: NICE. Neonatal parenteral nutrition. London: Nation Institute for Health and Clinical Excellence, 2020:NG154. https://www.nice.org.uk/guidance/ng154/evidence
76: O'Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control 2011;39(4 Suppl 1):S1-34. PMID 21511081
77: Osborn DA, Schindler T, Jones LJ, Sinn JK, Bolisetty S. Higher versus lower amino acid intake in parenteral nutrition for newborn infants. Cochrane Database Syst Rev 2018;3:CD005949. PMID 29505664
78: Park HW, Lee NM, Kim JH, Kim KS, Kim SN. Parenteral fish oil-containing lipid emulsions may reverse parenteral nutrition-associated cholestasis in neonates: a systematic review and meta-analysis. J Nutr 2015;145(2):277-83. PMID 25644348
79: Pasquel FJ, Spiegelman R, McCauley M, et al. Hyperglycemia during total parenteral nutrition: an important marker of poor outcome and mortality in hospitalized patients. Diabetes Care 2010;33(4):739-41. PMID 20040658
80: Patel P, Bhatia J. Total parenteral nutrition for the very low birth weight infant. Semin Fetal Neonatal Med 2018;22(1):2-7. PMID 27576106
81: Pichler J, Simchowitz V, Macdonald S, Hill S. Comparison of liver function with two new/mixed intravenous lipid emulsions in children with intestinal failure. Eur J Clin Nutr 2014;68(10):1161-7. PMID 24961544
82: Poindexter BB, Langer JC, Dusick AM, Ehrenkranz RA; National Institute of Child Health and Human Development Neonatal Research Network. Early provision of parenteral amino acids in extremely low birth weight infants: relation to growth and neurodevelopmental outcome. J Pediatr 2006;148(3):300-5. PMID 16615955
83: Poole RL, Hintz SR, Mackenzie NI, Kerner JA, Jr. Aluminum exposure from pediatric parenteral nutrition: meeting the new FDA regulation. JPEN J Parenter Enteral Nutr 2008;32(3):242-6. PMID 18443135
84: Porcelli PJ, Sisk PM. Increased parenteral amino acid administration to extremely low-birth-weight infants during early postnatal life. Pediatr Gastroenterol Nutr 2002;34(2):174-9. PMID 11840036
85: Premkumar MH, Carter BA, Hawthorne KM, King K, Abrams SA. High rates of resolution of cholestasis in parenteral nutrition-associated liver disease with fish oil-based lipid emulsion monotherapy. J Pediatr 2013;162(4):793-8. PMID 23164314
86: Puder M, Valim C, Meisel JA, et al. Parenteral fish oil improves outcomes in patients with parenteral nutrition-associated liver injury. Ann Surg 2009;250(3):395-402. PMID 19661785
87: Ramel S, Rao R. Hyperglycemia in extremely preterm infants. Neoreviews 2020;21(2):e89-e97. PMID 32005719
88: Rayyan M, Devlieger H, Jochum F, Allegaert K. Short-tern use of parenteral nutrition with a lipid emulsion containing a mixture of soybean oil, olive oil, medium-chain triglycerides, and fish oil: a randomized double-blind study in preterm infants. JPEN J Parenter Enteral Nutr 2012;36(1 Suppl):81S-94S. PMID 22237883
89: Repa A, Binder C, Thanhaeuser M, et al. A mixed lipid emulsion for prevention of parenteral nutrition associated cholestasis in extremely low birth weight infants: a randomized clinical trial. J Pediatr 2018;194:87-93. PMID 29269199
90: Robinson DT, Carlson SE, Murthy K, Frost B, Li S, Caplan M. Docosahexaenoic and arachidonic acid levels in extremely low birth weight infants with prolonged exposure to intravenous lipids. J Pediatr 2013;162(1):56-61. PMID 22878111
91: Rubinos LH, Ruth JS, Hawthorne K, Abrams SA. Reducing soy-based lipid concentration may not prevent the need for omega-3 therapy in parenteral nutrition associated cholestasis. Boston, MA: Pediatric Academic Society, 2012:E-PAS2012:3830.369.
92: Schulman J, Stricof R, Stevens TP, et al. Statewide NICU central-line-associated bloodstream infection rates decline after bundles and checklists. Pediatrics 2011;127(3):436-44. PMID 21339265
93: Sengupta A, Lehmann C, Diener-West M, Perl TM, Milestone AM. Catheter duration and risk of CLA-BSI in neonates with PICCs. Pediatrics 2010;125(4);648-53. PMID 20231192
94: Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 2002;21(6):495-505. PMID 12480795
95: Stephens BE, Walden RV, Gargus RA, et al. First week protein and energy associated with 18-month developmental outcomes and extremely low birth weight infants. Pediatrics 2009;123(5):1337-43. PMID 19403500
96: Stout SM, Cober MP. Metabolic effects of cyclic parenteral nutrition infusion in adults and children. Nutr Clin Pract 2010;25(3):277-81. PMID 20581322
97: Suganuma H, Bonney D, Andersen CC, et al. The efficacy and safety of peripheral intravenous parenteral nutrition vs 10% glucose in preterm infants born 30 to 33 weeks' gestation: a randomised controlled trial. BMC Pediatr 2020;20(1):384. PMID 32799841
98: Sunehag AL, Haymond MW. Glucose extremes in newborn infants. Clin Perinatol 2002;29(2):245-60. PMID 12168240
99: Takada M, Shimada M, Hosono S. Trace elements and mineral requirements for very low birth weight infants in rickets of prematurity. Early Hum Dev 1992;29:333-8.
100: te Braake FW, van den Akker CH, Riedijk MA, van Goudoever JB. Amino acid administration to premature infants directly after birth. J Pediatrics 2005;147(4)457-61. PMID 16227030
101: te Braake FWJ, van den Aaker CHP, Riedijk MA, van Goudoever JB. Parenteral amino acid and energy administration to preterm infants in early life. Semin Fetal Neonatal Med 2007;12(1):11-8. PMID 17142119
102: Thureen PJ, Melara D, Fennessey PV, Hay WW Jr. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res 2003;53(1):24-32. PMID 12508078
103: Tomasik PJ, Sztefko K. Effect of enteral and parenteral feeding on secretion of orexigenic peptides in infants. BMC Gastroenterol 2009:29(6):428-32. PMID 20003268
104: Tomsits E, Pataki M, Tölgyesi A, Fekete G, Rischak K, Szollár L. Safety and efficacy of a lipid emulsion containing a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish oil: a randomised, double-blind clinical trial in premature infants requiring parenteral nutrition. J Pediatr Gastroenterol Nutr 2010;51(4):514-21. PMID 20531018
105: Trivedi A, Sinn J. Early versus late administration of amino acids in preterm infants receiving parenteral nutrition. Cochrane Database Syst Rev 2013;(7):CD008771. PMID 23881744
106: Tyson JE, Kennedy KA. Trophic feedings for parenterally fed infants. Cochrane Database Syst Review 2005;(3):CD000504. PMID 16034854
107: Valentine, Fernandez S, Rogers LK, et al. Early administration of amino acids improves preterm infant weight. J Perinatol 2009;29(6):428-32. PMID 19444236
108: van den Akker CH, te Braake FW, Weisglas-Kuperus N, van Goudoever JB. Observational outcome results following a randomised controlled trial of early amino acid administration in preterm infants. J Pediatr Gastroenterol Nutr 2014;59(6):714-9. PMID 25187104
109: van Goudoever JB, Carnielli V, Darmaun D, Saiz de Pipaon M, ESPGHAN/ESPEN/ESPR/CSPEN working group on pediatric parenteral nutrition. ESPGHAN/ESPEN/ESPR guidelines on pediatric parenteral nutrition: amino acids. Clin Nutr 2018;37(6 Pt B):2315-23. PMID 30100107
110: van Kempen A, Eskes PF, Nuytemans D, et al. Lower versus traditional treatment threshold for neonatal hypoglycemia. N Engl J Med 2020;382(6):534-44. PMID 32023373
111: van Puffelen E, Hulst JM, Vanhorebeek I, et al. Effect of late versus early initiation of parenteral nutrition on weight deterioration during PICU stay: Secondary analysis of the PEPaNIC randomised controlled trial. Clin Nutr 2020;39(1):104-9. PMID 30879734
112: van Puffelen E, Vanhorebeek I, Joosten KF, Wouters PJ, Van den Berghe G, Verbruggen S. Early versus late parenteral nutrition in critically ill, term neonates: a preplanned secondary subgroup analysis of the PEPaNIC multicentre, randomised controlled trial. Lancet Child Adolesc Health 2018;2(7):505-15. PMID 30646158
113: Verstraete S, Verbruggen SC, Hordijk JA, et al. Long-term developmental effects of withholding parenteral nutrition for 1 week in the paediatric intensive care unit: a 2-year follow-up of the PEPaNIC international, randomised, controlled trial. Lancet Respir Med 2019;7(2):141-53. PMID 30224325
114: Vlaardingerbroek H, Veldhorst MA, Spronk S, van den Akker CH, van Goudoever JB. Parenteral lipid administration to very-low-birth-weight infants—early introduction of lipids and use of new lipid emulsions: a systematic review and meta-analysis. Am J Clin Nutr 2012;96(2):255-68. PMID 22743312
115: Vlaardingerbroek H, Vermeulen MJ, Carnielli VP, Vaz FM, van den Akker CH, van Goudoever JB. Growth and fatty acid profiles of VLBW infants receiving a multicomponent lipid emulsion from birth. J Pediatr Gastroenterol Nutr 2014;58(4):417-27. PMID 24667866
116: Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding, American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008;122(5):1142-52. PMID 18977996
117: Webbe JWH, Longford N, Battersby C, et al. Outcomes in relation to early parenteral nutrition use in preterm neonates born between 30 and 33 weeks' gestation: a propensity score matched observational study. Arch Dis Child Fetal Neonatal Ed 2022;107(2):131-6. PMID 30224325
118: Wendel D, Mezoff EA, Raghu VK, et al. Management of central venous access in children with intestinal failure: a position paper from the NASPGHAN Intestinal Rehabilitation Special Interest Group. J Pediatr Gastroenterol Nutr 2021;72(3):474-86. PMID 33399327
119: Willis TC, Carter BA, Rogers SP, Hawthorne KM, Hicks PD, Abrams SA. High rates of mortality and morbidity occur in infants with parenteral nutrition-associated cholestasis. JPEN J Parenter Enteral Nutr 2010;34(1):32-7. PMID 19587385
120: Zamir I, Tornevi A, Abrahamsson T, et al. Hyperglycemia in extremely preterm infants-insulin treatment, mortality and nutrient intakes. J Pediatr 2018;200:104-10 e1. PMID 29731360
121: Ziegler EE, O’Donnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth 1976;40(4):329-41. PMID 1010389

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Ian Griffin MD

Dr. Griffin of Mid-Atlantic Neonatal Associates has no relevant financial relationships to disclose.
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Editor

Bernard L Maria MD

Dr. Maria of Thomas Jefferson University has no relevant financial relationships to disclose.
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Former Authors

Dilip M Purohit MD
Carolyn A Weiglein MS
W Jason Parker MD
Catalina Bazacliu MD
Noe R Saravia-Torres MD
Ann Simonin MD
Amy Thompson MD
Quyen Pham MD
Pinkal Patel MD
Jatinder Bhatia MD
Kelsey Moorman DO

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Parenteral nutrition in infants and children

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Nutrition and the brain

Clinical Categories

General Child Neurology

Parenteral nutrition in infants and children

Parenteral nutrition in infants and children

Introduction

Overview

Key points

Historical note and terminology

Clinical aspects

Description

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

Table 2. Daily Electrolyte and Mineral Requirement for Pediatric Patients

Indications

Contraindications

Outcomes

Adverse effects

Table 3. Complications of Total Parenteral Nutrition

Special considerations

Scientific basis

References

Contributors

Author

Editor

Former Authors

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Parenteral nutrition in infants and children

Introduction

Overview

Key points

Historical note and terminology

Clinical aspects

Description

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

Table 2. Daily Electrolyte and Mineral Requirement for Pediatric Patients

Indications

Contraindications

Outcomes

Adverse effects

Table 3. Complications of Total Parenteral Nutrition

Special considerations

Scientific basis

References

Contributors

Author

Editor

Former Authors

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Acute cerebellar ataxia in children

Zika virus: neurologic complications

Cerebral edema in childhood

CNS germinoma

Vein of Galen malformations

Patent foramen ovale

Migraine in childhood

Neonatal opioid withdrawal syndrome

This is an article preview.
Start a Free Account
to access the full version.