Parenteral Nutrition in the Neonatal Intensive Care Unit Nahed O. ElHassan and Jeffrey R.

Kaiser Neoreviews 2011;12;e130 DOI: 10.1542/neo.12-3-e130

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Article

parenteral nutrition

Parenteral Nutrition in the Neonatal Intensive Care Unit

Nahed O. ElHassan, MD, MPH,* Jeffrey R. Kaiser, MD, MA

Abstract
Neonatal parenteral nutrition (PN) is readily available in many hospitals and plays an essential role in the management of sick and growing preterm and term infants. PN can be used as the sole source of nutrition support for infants who cannot be fed or as an adjunct to enteral feeding. Preterm infants are a particularly vulnerable population because they are born at a time, if they had remained in utero, of rapid intrauterine brain and body growth. The impact of early malnutrition can have long-lasting negative effects on central nervous system development and growth. Despite this, PN is often provided to preterm infants based on local traditions rather than experimental evidence. The quality of PN and its early initiation are critical in providing the most adequate substrates for appropriate development. This article reviews the energy and uid requirements of infants and presents by component (protein, carbohydrates, lipids, minerals such as calcium and phosphorus, trace elements, and multivitamins) the available literature on neonatal PN and its complications. In addition, suggested guidelines for PN administration for preterm and term neonates are presented.

Author Disclosure Drs ElHassan and Kaiser have disclosed no nancial relationships relevant to this article. This commentary does contain a discussion of an unapproved/ investigative use of a commercial product/device.

Objectives
1. 2. 3. 4.

After completing this article, readers should be able to:

Describe the different components of PN for neonates. Review the suggested recommendations for macro/micronutrients in PN for neonates. Understand the function and benets of macro/micronutrients in PN for neonates. Discuss the neonatal morbidities and possible complications associated with each of the PN components.

Introduction
Neonatal PN was rst used in 1967 for an infant who had intestinal atresia and postoperative weight loss. (1) The goal of PN in preterm neonates has been to approximate the nutrition they would have received if they have remained in utero for appropriate extrauterine growth and development. (2) PN can be used as the sole source of nutrition support for Abbreviations neonates who cannot be fed or as an adjunct to enteral AA: amino acid feeding. Since its implementation, many lessons have been ALA: alpha-linolenic acid learned about the benets and complications of PN. An BUN: blood urea nitrogen important milestone in neonatal nutrition research was the Ca: calcium realization of the valuable impact of early initiation on EFAD: essential fatty acid deciency neurocognitive development. Despite this fact, the clinical ELBW: extremely low birthweight practice of providing PN is often based on local tradition and FDA: United States Food and Drug Administration dogma rather than experimental evidence. (2)(3) Although FFA: free fatty acid fetuses receive continuous nutrition from the placenta LA: linoleic acid through the umbilical vein, many preterm newborns have P: phosphorus essential nutrients limited or entirely withheld due to PN: parenteral nutrition theoretical concerns and previous experiences with older VLBW: very low birthweight PN preparations. The quality of PN and its early initiation are critical in providing the most appropriate substrates for
*Assistant Professor of Pediatrics, Department of Pediatrics, Neonatology, University of Arkansas for Medical Sciences, College of Medicine, Arkansas Childrens Hospital, Little Rock, AR. Associate Professor, Departments of Pediatrics and Obstetrics and Gynecology, Neonatology, University of Arkansas for Medical Sciences, College of Medicine, Arkansas Childrens Hospital, Little Rock, AR. e130 NeoReviews Vol.12 No.3 March 2011

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appropriate growth and development. (2)(3) This article aims to discuss the art and science of PN in neonates and reviews the benets and potential complications of the multiple components provided in PN for preterm and term neonates. When there is limited evidence, and recommendations are made, this is stated. Denitions of preterm infants for this article are stated in Table 1.

Energy Requirements
Knowing the appropriate energy requirements for neonates is fundamental in prescribing PN. Energy is essential for body maintenance and growth. The basal resting metabolic rate reects the energy expenditure required for maintenance of vital processes. The resting metabolic rate has been estimated to be 40 to 60 kcal/kg per day in parenterally fed neonates maintained in a thermoneutral environment. (4) Each gram of weight gain for growth, including the stored energy and the energy costs of component synthesis, requires between 3 and 4.5 kcal. (4) Thus, an ideal daily weight gain of 15 g/kg (which estimates daily fetal growth) requires an additional caloric requirement of 45 to 67 kcal/kg above the estimated resting metabolic rate. (4) A summary of the energy requirements during the neonatal period is presented in Table 2. These estimated energy requirements have been calculated in healthy growing preterm infants at 3 to 4 weeks of age. There is relatively minimal information, however, on the energy requirements for sick infants and especially extremely low-birthweight (ELBW) infants during early postnatal life. ELBW infants are believed to have increased metabolic demands due to their large body proportion of metabolically active organs, including the heart, liver, kidney, and brain. (4)

of 60 mL/kg per day to meet maintenance uid needs (replacing net losses). As infants mature, uid needs gradually increase to a total of 120 to 150 mL/kg per day to allow for increased renal solute load, stool water output, and growth. (5) Preterm infants have more insensible water losses than term infants due to their large surface area, skin immaturity, and ensuing increased evaporation. Thus, uid needs are higher on the rst postnatal day at 80 to 100 mL/kg per day and increase by 10 to 20 mL/kg per day to a total of 130 to 180 mL/kg per day as preterm infants mature (Table 2). (5)

Infusion Routes
PN may be infused via peripheral and central catheters. Peripheral infusion typically is used for short-term nutrition support. Peripheral vein osmolarity tolerance ranges from 700 to 1,000 mOsm/L. Osmolarity is calculated using the equation: (6) osmolarity (mOsm/L)([amino acids (g/L) 8] [glucose (g/L) 7] [sodium (mEq/L) 2] [phosphorus (mg/L) 0.2] 50) The osmolarity of glucose solutions rises from 255 to 1,020 mOsm/L with increasing concentration from 5% to 20%, respectively. Generally, glucose concentrations of 12.5% or less are well tolerated by peripheral veins as long as no other osmolarity-increasing agents are added. Central infusion of PN is delivered via central venous catheters and is the preferred route for long-term PN.

Components of Parenteral Nutrition (Table 2)

Protein
Previously used intravenous amino acid (AA) preparations were based on casein hydrolysates. Current crystalline AA solutions have elevated ratios of essential to nonessential AAs, leading to the endogenous production of higher concentrations of the branch amino acids: leucine, isoleucine, and valine. (7) Despite extensive endeavors to create optimized AA preparations, however, plasma AA concentrations in infants receiving current intravenous solutions are still reduced compared with breastfed infants. (8) This is partly due to the poor solubility or stability of various intravenous AAs (eg, glutamine, tyrosine, and cysteine). (8) Cysteine is often considered a semi-essential AA in the newborn period and is, therefore, routinely added to AA preparations to circumvent low cysteine synthesis, low plasma concentrations, and impaired protein synthesis. (9) Cysteine is a major substrate for glutathione, a tripeptide (glutamic acid/cysteine/glycine) antioxidant, and is important in maintaining redox potential and calcium homeostasis.
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Fluid Requirements
The percentage of total body water in fetuses decreases from approximately 95% early in development to 80% by 8 months gestation and to 75% at term. (5) During the rst day after birth, term infants require a minimum

Table 1.

Classication of Preterm Infants

Preterm infants are born <37 weeks gestation. Low-birthweight infants weigh <2,500 g at birth. Very low-birthweight infants weigh <1,500 g at birth. Extremely low-birthweight infants weigh <1,000 g at birth.

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parenteral nutrition

Table 2.

Suggested Recommendations for Parenteral Nutrition Macronutrients for Neonates

Advancement Term Preterm Term Preterm 10 to per 10 to per 20 mL/kg day 20 mL/kg day Goal Neonate Blood Concentration Potential Complications

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Source

Initial Administration

60 to per 80 to per Total Energy Intake

Fluid

70 mL/kg day 100 mL/kg day

Energy Expended

Resting metabolic rate Activity Thermoregulation Synthesis Energy Excreted Energy Stored

Amino Acids1

Cholestasis

Dextrose

2 2 8

130 to 150 mL/kg per day 130 to 180 mL/kg per day 90 kcal/kg per day 120 kcal/kg per day 40 to 60 kcal/kg per day 40 to 50 kcal/kg per day 0 to 5 kcal/kg per day 0 to 5 kcal/kg per day 15 kcal/kg per day 15 kcal/kg per day 20 to 30 kcal/kg per day to 3 g/kg per day 1 g/kg per day 3 g/kg per day to 3 g/kg per day 0.5 to 1 g/kg per day 3.5 to 4 g/kg per day mg/kg per minute 1 to 3 mg/kg 12 mg/kg per minute per minute to 6 mg/kg per 1 to 3 mg/kg 12 mg/kg per minute minute2 per minute Term Preterm Term >45 to <150 to 220 mg/dL Preterm >45 to <150 to 220 mg/dL

Fat3

2 to 3 g/kg per day 2 to 3 g/kg per day

0.5 to 1 g/kg per day 3 to 3.5 g/kg per day 0.5 to 1 g/kg per day 3 to 3.5 g/kg per day

Term <150 to 250 mg/dL4 Preterm <150 to 250 mg/dL4

Hyperglycemia is associated with: 1. Death 2. Prolonged hospital stay 3. Intraventricular hemorrhage Grade 3 & 4 4. Necrotizing entercolitis 5. Sepsis Cholestasis

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Early and aggressive delivery of amino acids does not lead to the development of azotemia, hyperammonemia, or metabolic acidosis. Glucose infusion rate is sometimes limited to 4 mg/kg per minute in extremely low-birthweight infants who have hyperglycemia. 3 20% intravenous fat emulsions are typically used and infused over 24 hours to maximize clearance. 4 Some drugs (eg, amphotericin B and steroids) lead to elevated triglyceride concentrations.

parenteral nutrition

(9) Because the inclusion of cysteine in AA solutions is technically difcult due to its low solubility, it is typically added last to the solution at a dose of 30 to 40 mg/g AA. Cysteine also decreases the pH of AA solutions and reduces calcium and phosphorus precipitation. (10) Protein accretion rates by fetuses at 24 to 25 weeks, 27 to 28 weeks, and 30 to 32 weeks gestation have been estimated to be 4.0, 3.6, and 3.3 g/kg per day, respectively. (11)(12) Infusion of AA with glucose as early as the rst postnatal day decreases protein catabolism and enhances net protein accretion. (13)(14) Thus, reducing the number of hours that infants receive suboptimal nutrition (without AAs) has been emphasized recently as an important goal of neonatal intensive care. (13)(14) (15) The purpose of early AA supplementation is to provide preterm infants with substrate that promotes protein deposition that closely approximates fetal energy production and growth. (13) For most preterm infants, 1.0 to 1.5 g/kg per day of intravenous AA along with glucose prevents protein catabolism. (15) When nonprotein energy intake is 80 to 85 kcal/kg per day and AA intake is 2.7 to 3.5 g/kg per day, nitrogen retention and growth might actually approach the intrauterine rate. (16) Recent studies have challenged the older practice of starting at 0.5 to 1 g/kg per day of AA and gradually advancing the AA infusion rate. (13)(14)(15)(16)(17) (18) In a retrospective study, Valentine and associates (13) suggested that providing 3 g/kg per day of AA within 24 hours of birth to very low-birthweight (VLBW) infants was safe and associated with better weight gain and shorter duration of PN administration. ELBW infants may require up to 4 g/kg per day of intravenous AA to maintain stores and promote growth. (15) More research is needed to establish the optimal AA requirements in critically ill infants and in those who have sepsis and renal and hepatic dysfunction. The major concerns about early and aggressive delivery of AA, especially to ELBW infants, are the development of azotemia, hyperammonemia, and metabolic acidosis. These complications of PN were reported using earlier AA preparations and rarely occur with current crystalline solutions. Blood urea nitrogen (BUN) represents the complex interaction of hydration status, renal function, energy quality and quantity, and degree of illness. (19)(20)(21) Rising BUN values are, therefore, not just a reection of the ELBW infants intolerance to AA infusion. (19)(20)(21) In fact, studies of fetal AA oxidation suggest that higher BUN reects appropriate AA utilization for both energy and lean mass production. In addition, metabolic acidosis during the rst postnatal week occurs independently of the duration and amount

of AA delivery. (20) Metabolic acidosis in VLBW infants can be caused by multiple factors (eg, defects of urinary acidication, acute illness, hypotension, poor perfusion) and cannot be solely attributed to AA administration. (21) Prolonged exposure to intravenous AA solutions does contribute to the development of PN-associated cholestasis. (22)

Carbohydrate
Glucose is transported across the placenta via facilitated diffusion and is the principal energy substrate for the fetus. The primary storage form of glucose is glycogen, which is only produced during the third trimester. Glucose is the chief energy source for the neonatal brain and is of paramount importance for preterm infants who, in addition to having limited glycogen stores, also have especially metabolically active organs. (7) Endogenous glucose production varies with age and was estimated to be 8 mg/kg per minute in term newborns and 6 mg/kg per minute in preterm infants. (23)(24) These production rates provide an appropriate starting point for glucose infusion rates in PN for term and preterm infants. The upper rate of glucose administration is dictated by the maximal glucose oxidative capacity for energy production and glycogen deposition. When glucose is given in excess, it is converted into lipid via lipogenesis. This conversion is inefcient, increases energy expenditure, and may have additional clinical consequences via increased carbon dioxide production and exacerbation of lung disease. (23)(25)(26) The maximum glucose oxidation capacity is 12 mg/kg per minute in term newborns and preterm infants receiving long-term PN (27) and generally should not exceed this concentration. Gestational age and clinical status modify glucose oxidative capacity. For example, it has been estimated to be 7 mg/kg per minute in preterm infants during the rst 2 postnatal weeks and 5 mg/kg per minute in critically ill children who have burns. (28) The minimum recommended blood glucose concentration is 45 mg/dL (2.5 mmol/L). (8) Despite limited glycogen storage capacity, ELBW infants often experience episodes of hyperglycemia during the rst few postnatal days. This may be due to surges in glucose production caused by birth-related increases in catecholamines, possibly compounded by an exogenous supply of catecholamines and inotropic drugs, a decrease in endogenous production of insulin, and an increase in peripheral and hepatic insulin resistance. (7) In addition, ELBW infants often fail to suppress endogenous glucose production completely in response to an exogenous supply of PN glucose. (29) Although there is no consensus
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denition of hyperglycemia, especially in ELBW infants, a suggested range may be 150 to 220 mg/dL (8.3 to 12.2 mmol/L). (29) The primary concern for hyperglycemia in infants is its association with death, prolonged hospitalization, intraventricular hemorrhage grades 3 and 4, necrotizing enterocolitis, and late-onset bacterial and fungal sepsis. (29) Early AA supplementation on the rst day after birth seems to stabilize high blood glucose concentrations by stimulating endogenous insulin secretion. (7) Other interventions for hyperglycemia include reducing the glucose infusion rate or treating with intravenous insulin. (29) Of note, a Cochrane review evaluating these two strategies for treatment of hyperglycemia found no difference in death or serious morbidities. (29) A randomized trial in preterm infants who have hyperglycemia needs to be conducted to address this question. There is also a concern about the potential risk of lactic acidemia in infants receiving high insulin and glucose administration. (7) Because the safety of insulin therapy and its impact on hyperglycemia-related morbidities have not been established, the consensus in the literature points toward incrementally decreasing the glucose infusion rate to approximately 4 mg/kg per minute and reserving insulin use for infants whose blood glucose concentrations are greater than 250 mg/dL (13.9 mmol/L) while receiving this infusion rate.

Lipids
Lipid emulsions are especially important components of neonatal PN because they supply an energy source that has low osmolarity and high energy content per unit volume. (30) Intravenous fat emulsions currently available in the United States are 10% (1.1 kcal/mL) or 20% (2 kcal/mL) soy or soy/safower oil-based emulsions. (30) The 10% emulsion is typically not used because it contains high amounts of phospholipids that can contribute to hyperphospholipidemia and subsequent hypercholesterolemia. (8) It is crucial to provide a minimum of 0.5 to 1.0 g/kg per day of lipids to prevent essential fatty acid deciency (EFAD), which can develop in preterm infants during the rst postnatal week and as early as the second day after birth. (8)(18)(30)(31) Essential fatty acids have double bonds in the -6 and -3 positions and cannot be synthesized endogenously by humans. (31) Therefore, specic -6 and -3 fatty acids or their precursors with double bonds at these positions (ie, linoleic acid [LA, 18:2 -6] and alpha-linolenic acid [ALA, 18:3 -3]) must be provided in PN. (12) LA and ALA have critical roles in postnatal brain development. EFAD is associated
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with poor growth, scaly skin lesions, and visual and neurologic abnormalities and has been observed in infants who have been maintained for several weeks on PN without essential fatty acids. Because lipids are the primary source of energy supply in PN, inadequate lipid intake can lead to caloric undernutrition and proteolysis. (32)(33) Although it has been common practice to increase lipid intake incrementally over several days in preterm infants requiring PN, there is no scientically valid argument why these newborns should not be offered 2 to 3 g/kg per day of AA and 2 to 3 g/kg per day of lipids immediately after birth. In fact, it has been shown that provision of 3.5 g/kg per day of AA and 3 g/kg per day of lipids within the rst 24 hours of birth to VLBW infants was well tolerated and without adverse effects. (34) In addition, despite phobias about beginning lipids early, a Cochrane meta-analysis reported no increased risk of necrotizing enterocolitis, sepsis, thrombocytopenia, or signicant jaundice or increased duration of ventilation when lipids were introduced early (12 hours) versus later (6 days). (35) Moreover, several investigators have shown that infants treated with the traditional practices of restricted protein supplementation and limited energy supply during the immediate postnatal period had signicant postnatal growth restriction and poor neurodevelopmental outcomes. (36)(37)(38) Ehrenkranz and associates (37) showed that increased growth velocity in ELBW newborns (presumably due to better nutrient intake) exerts a signicant positive inuence on neurodevelopment and growth outcomes at 18 to 22 months corrected age. In addition, preterm infants who had increased energy supply during the rst postnatal week have been shown to have a 4.6-point increase in Bailey Mental Development Index for each additional 10 kcal/kg per day they received. (36) Although data showing the specic benets of early initiation of lipids are limited, early and aggressive supplementation has not been associated with increased adverse effects. Lipids may be initiated early during the rst day after birth at doses of more than 1 to 2 g/kg per day to increase energy supply and improve long-term growth and neurodevelopment. The maximum lipid dose is determined by an infants ability to metabolize fat emulsions. (30) Lipoprotein lipase in the capillary endothelium of extrahepatic tissues, hepatic lipase in the endothelium of hepatic capillaries, and lecithin cholesterol acyltransferase are the three enzymes that determine the rate of PN lipid clearance. (39) Although high doses of heparin can stimulate lipoprotein lipase activity, heparin infusion does not improve the utilization of intravenous lipids because it also causes an

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increase in free fatty acids (FFAs) beyond the infants clearance ability. (40) Intravenous lipids should be infused over 24 hours to maximize clearance. (13) When the lipid infusion rate exceeds hydrolysis rates, concentrations of plasma triglycerides and FFAs increase. Although there is no clear consensus in the literature, current recommendations for maximal plasma triglyceride concentrations range between 150 mg/dL and 250 mg/dL. (7)(13)(18)(30) Some drugs and medical conditions lead to elevated serum triglyceride concentrations. (30) Liposomal amphotericin B contains fat emulsion (30) and steroids, such as hydrocortisone, that can lead to transient increases in triglyceride concentrations. (30) Carnitine facilitates the transport of long-chain fatty acids across the mitochondrial membrane, making them available for beta-oxidation. (40) Studies evaluating carnitine supplementation in infants and children, however, have yielded controversial results. Carnitine concentrations decrease during prolonged carnitine-free PN, especially in immature preterm infants, (40) but a metaanalysis showed no benet of carnitine supplementation on lipid tolerance, ketogenesis, or weight gain in infants requiring PN. (41) Nonetheless, carnitine supplementation at 2 to 10 mg/kg is recommended in infants exclusively receiving PN for more than 4 weeks. (18) Intravenous fat emulsions used in the United States are comprised of either soybean oil or a combination of safower and soybean oil and are rich in proinammatory -6 fatty acids. (42) Many clinicians believe that the high -6 content of these fat emulsions contribute to PNassociated cholestasis. (43) Another fat emulsion prepared from sh oils that is not yet approved for use in the United States has been shown to reverse cholestasis in infants six times faster than in those receiving soybean oil-based fat emulsions, probably because this emulsion has -3 fatty acids that have anti-inammatory properties. (43)(44) In addition, use of the sh oils emulsion is not associated with hypertriglyceridemia, coagulopathy, or EFAD. (43)(44) Currently, this emulsion can only be prescribed in the United States via United States Food and Drug Administration (FDA) compassionate approval.

Calcium (Ca) and Phosphorus (P)

Although there is no consensus on optimal parenteral requirements for Ca and P, the third-trimester fetal accretion rates of 3.5 mmol/kg per day (140 mg/kg per day) for Ca and 2.4 mmol/kg per day (75 mg/kg per day) for P are often used. (11) Fetal accretion rates peak during the third trimester, with upwards of 80% of fetal

skeletal mineralization taking place during this period. (11) Thus, the goal of PN in preterm infants is to achieve intrauterine rates of bone mineralization, and preterm infants who lack part or all of the fetal third trimester are at increased risk of osteopenia. (8)(11)(18) Unfortunately, due to delayed establishment of full enteral feedings, prolonged PN, and chronic use of certain medications (diuretics and corticosteroids) that increase mineral excretion, attaining this goal is often very difcult. (11) Further, the ability to provide neonates with the recommended amounts of Ca and P has been limited in the United States by their precipitation in PN solution. (45) (46) The solubility of Ca and P are affected by pH, temperature, Ca and P concentrations, AA product and concentration, lipid emulsions, dextrose, and magnesium concentration. Another very critical component of Ca-P compatibility has been the type of phosphate salts used. Organic phosphate, used in Europe and Canada, has far superior compatibility with Ca salts than inorganic phosphate, approved for use in the United States. (45) (46) Organic phosphates consist of a phosphate group covalently bonded to an organic molecule such as glycerol, glucose, or fructose. The phosphate group, therefore, cannot be fully ionized and is much less available to interact with Ca. (46) As natural substrates for extracellular phosphatases, nutritional bioavailability of organic phosphates is assured. In addition, organic phosphates are well tolerated without signicant toxicity. (46) In the United States, P is typically supplemented as sodium phosphate, a constituent contaminated by aluminum. The FDA guidelines for aluminum content recommend PN components to have less than 4 to 5 g/kg per day. (47) Aluminum overexposure may cause hypochromic microcytic anemia, neurotoxicity, and metabolic bone disease in which infants chronically exposed to parenteral aluminum have reduced lumbar spine and hip bone mass during adolescence. (47)(48) Although it is difcult to adhere to the current FDA recommendations because of the high aluminum content in PN components, one method to reduce aluminum intake is to use sodium phosphate (9.5 mg of aluminum/mmol) rather than potassium phosphate (24 mg of aluminum/mmol). Ca in PN is typically provided as Ca gluconate, a safer choice than calcium chloride. (45) The 12-carbon organic gluconate salt of Ca is only partially ionized in aqueous solutions, and the degree of its dissociation decreases as the concentration increases. (45) This decrease in the availability of freely dissociated Ca ions is sufcient to reduce the potential for precipitation with phosphate ions. In contrast, the dissociation of Ca ions
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Table 3.

Trace Elements in Neonatal Parenteral Nutrition (PN)1

Zinc2 (g/kg per day) 400 200 100 Copper3 (g/kg per day) 20 20 20 Manganese3 (g/kg per day) 1.0 1.0 1.0 Chromium4,5 (g/kg per day) 0.05 to 0.2 0.2 0.14 to 0.2 Selenium2,5 (g/kg per day) 2 2 2

Dosing Category (weight) <3 kg >3 to 10 kg >10 to 15 kg

1 2

Molybdenum at 1 g/kg per day is recommended for low-birthweight infants receiving PN for more than 4 weeks. (11)(18) Infants who have short bowel syndrome lose signicant amounts of zinc and selenium in diarrhea and small bowel efuent, necessitating close monitoring of serum zinc and selenium. (11)(18) 3 Copper supplementation is limited to 10 g/kg per day, and no manganese is given to infants who have cholestasis. (11)(18) 4 Chromium is a contaminant of PN solutions that results in a 10% to 100% increase in amount of chromium delivered, necessitating serum chromium monitoring for infants receiving long-term PN. (11)(18) 5 No chromium or selenium supplementation is recommended for infants who have chronic renal failure. (11)(18)

from the inorganic chloride salt is constant, irrespective of its nal concentration.

Trace Elements
Trace mineral preparations are commercially available as single agents or as combination products. The trace elements currently recommended for neonatal PN are zinc, copper, manganese, chromium, selenium, and molybdenum. Although the optimum time to start trace elements supplementation has not undergone extensive
Table 4.

testing, most neonatologists begin supplementation within the rst few days after birth (11) and provide it daily in PN. A summary of trace element doses, functions, deciencies, and toxicities is shown in Tables 3 and 4. None of the combination preparations of neonatal trace elements meet the needs of every gestational or postnatal age or clinical condition, and manganese content may be up to ve times the recommended dose in the currently available combination preparations. (11)

Function, Deciencies, and Toxicities of Trace Elements

Function Important component of several enzymes (eg, carbonic anhydrase and carboxypeptidase), important for growth Reported Deciencies Failure to thrive, alopecia, diarrhea, dermatitis (commonly perianal), ocular changes, rash (crusted, erythematous, involving face, extremities, and anogenital areas), nail hypoplasia or dysplasia Anemia, osteoporosis, depigmentation of hair and skin, neutropenia, poor weight gain, hypotonia, and ataxia later in life Nausea, vomiting, dermatitis, hair depigmentation, growth retardation None Implicated in oxidative diseases such as bronchopulmonary dysplasia and retinopathy of prematurity, hypothyroidism, myopathy None

(11)(18)

Trace Elements Zinc

Reported Toxicities Depresses phagocytic and bacterial leukocytic activity, pancreatitis

Copper

Manganese

Chromium Selenium

Component of several enzymes such as cytochrome oxidase, superoxidase dismutase, monoamine oxidase, and lysyl oxidase Role in enzyme activation (eg, superoxide dismutase), important for normal bone structure, role in carbohydrate metabolism Role in carbohydrate and lipid metabolism, regulator of insulin action Component of glutathione peroxidase, important in thyroid metabolism Essential for several enzymes involved in DNA metabolism

Hepatic cirrhosis

Basal ganglia damage, neurotoxicity, cholestasis Chronic renal failure None

Molybdenum

Interferes with copper metabolism

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Manganese neurotoxicity is a special concern for infants (18) because the element may be deposited in the basal ganglia. (49) Excessive intakes of parenteral manganese may also induce PN-associated liver disease. (49) Therefore, individual trace elements should be used in neonatal PN instead of combination products at this time.

Conclusion
The nutritional management of term and preterm neonates presents a constant challenge in adapting an approach that maximizes both short- and long-term outcomes while reducing morbidities. In addition, many clinicians still prescribe PN based on local dogma and outdated concerns. Although substantial experimental evidence has been acquired in recent years, there are still many gaps of knowledge in the provision of the most optimal neonatal intravenous nutrition, especially for extremely preterm infants. As is evident in this review, further research and evaluation are needed in many areas of neonatal PN, such as the most appropriate approach to treat hyperglycemia in the rst few postnatal days in ELBW infants, the safety of providing early aggressive intravenous lipids, the optimal time to add multivitamins or trace elements to intravenous PN, and the impact of protecting PN from light exposure. In addition, other problems must be dealt with by the manufacturers, including producing combination trace elements packages that meet the needs of all neonates and reducing aluminum content of PN components. Hopefully, over time, the previously noted suggested PN guidelines will be challenged by new and emerging knowledge and research, and clinicians will initiate and advance PN according to this evidence rather than local lore.

Multivitamins
Although the optimal time to begin vitamin supplementation in PN is unknown, most practitioners administer them within the rst few days of birth and provide them on a daily basis. Preterm infants are especially at risk for vitamin deciency due to their poor vitamin stores and increased requirement for rapid growth. (11) A summary of multivitamin doses and composition is presented in Table 5. The clinical impact of free radicals, which can develop in intravenous multivitamin preparations, has been evaluated. (50) Hydrogen peroxide and other peroxides are generated in light-exposed PN. Light-sensitized riboavin available in parenteral multivitamin preparations catalyzes electron transfer between electron donors, such as vitamin C, AA, or lipids and oxygen dissolved in PN solution. (50) Shielding PN from light has been associated with a decreased risk of death or bronchopulmonary dysplasia and with lower triglyceride concentrations. (50) The amount of hydrogen peroxide infused with PN can be reduced by half when the entire PN solution and delivery system (ie, PN constituents, dextrose bag, lipid syringe, and tubing) is light-protected. As an alternative, studies in animals have shown that the mixture of multivitamins with lipid emulsion can dramatically decrease the generation of lipid peroxides and protect against the loss of antioxidant vitamins. (50) Light protection of PN, however, is not currently widely used in neonatal intensive care units.

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specications

Know the caloric requirements for optimal postnatal growth of preterm and term infants, accounting for caloric expenditures needed for physical activity and maintenance of bodily temperature. Distinguish between indispensable, essential, and non-essential amino acids. Know the protein requirements of preterm and full-term infants. Know the fat requirements of preterm and full-term infants. Know the carbohydrate requirements for preterm and fullterm infants. Know the changing requirements of calcium and phosphorous by the neonate at various gestational ages. Know the requirements for vitamins in newborn infants, and the differences between preterm and full-term infants. Know the clinical manifestations, diagnosis, management, and prevention of zinc, copper, selenium, manganese, and chromium deciency. Know the nutritional composition of parenteral solutions. Recognize the relationship between the calcium and phosphorus content of parenteral nutrition solutions and osteopenia.

Daily Dose Recommendations for Pediatric Multivitamins

Table 5.

(18)*
Dose 1.5 mL 3.25 mL 5 mL

Weight <1 kg 1 to 3 kg >3 kg

*Assumes normal age-related organ function. Pediatric multivitamin formulation (5 mL): Vitamin A, 2,300 IU; Vitamin D, 400 IU; Vitamin E, 7 IU; Vitamin K, 200 g; Ascorbic acid, 80 mg; Thiamine, 1.2 mg; Riboavin, 1.4 mg; Niacin, 17 mg; Pantothenic acid, 5 mg; Pyridoxine, 1 mg; Cyanocobalamin, 1 g; Biotin, 20 g; Folic acid, 140 g.

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References
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neonates with birthweight less than 1250 g. J Perinatol. 2005;25: 130 133 20. Radmacher PG, Lewis SL, Adamkin DH. Early amino acids and the metabolic response of ELBW infants ( 1000 g) in three time periods. J Perinatol. 2009:29:433 437 21. Roggero P, Gianni ML, Morlacchi L, et al. Blood urea nitrogen concentrations in low-birth-weight preterm infants during parenteral and enteral nutrition. J Pediatr Gastroenterol Nutr. 2010;51:213215 22. Brown MR, Thunberg BJ, Golub L, Maniscalco WM, Cox C, Shapiro DL. Decreased cholestasis with enteral instead of intravenous protein in the very low birth weight infant. J Pediatr Gastroenterol Nutr. 1989;9:2127 23. Kalhan SC, Kilic I. Carbohydrate as nutrient in the infant and child: range of acceptable intake. Eur J Clin Nutr. 1999;53:S94 S100 24. Sunehag A, Ewald U, Larsson A, Gustafsson J. Glucose production rate in extremely immature neonates ( 28 weeks) studied by use of deuterated glucose. Pediatr Res. 1993;33:97100 25. Nose O, Tipton JR, Ament ME. Effect of the energy source on changes in energy expenditure, respiratory quotient, and nitrogen balance during total parenteral nutrition in children. Pediatr Res. 1987;21:538 541 26. Forsyth JS, Murdock N, Crighton A. Low birthweight infants and total parenteral nutrition immediately after birth. III. Randomized study of energy substrate utilisation, nitrogen balance, and carbon dioxide production. Arch Dis Child Fetal Neonatal Ed. 1995;73:F13F16 27. Jones MO, Pierro A, Hammond P, Nunn A, Lloyd DA. Glucose utilization in the surgical newborn infant receiving total parenteral nutrition. J Pediatr Surg. 1993;28:11211125 28. Lafeber HN, Sulkers EJ, Chapman TE, Sauer PJ. Glucose production and oxidation in preterm infants during total parenteral nutrition. Pediatr Res. 1990;28:153157 29. Bottino M, Cowett RM, Sinclair JC. Interventions for treatment of neonatal hyperglycemia in very low birth weight infants. Cochrane Database Syst Rev. 2009;21:CD007453 30. Shulman RJ, Philips S. Parenteral nutrition in infants and children. J Pediatr Gastroenterol Nutr. 2003;36:587 607 31. Innis SM. Essential fatty acids in growth and development. Prog Lipid Res. 1991;30:39 103 32. Auestad N, Halter R, Hall RT, et al. Growth and development in term infants fed long-chain polyunsaturated fatty acids: a double-masked, randomized, parallel, prospective, multivariate study. Pediatrics. 2001;108:372381 33. Auestad N, Scott DT, Janowsky JS, et al. Visual, cognitive, and language assessments at 39 months: a follow-up study of children fed formulas containing long-chain polyunsaturated fatty acids to 1 year of age. Pediatrics. 2003;112:e177 e183 34. Ibrahim HM, Jeroudi MA, Baier RJ, Dhanireddy R, Krouskop RW. Aggressive early total parenteral nutrition in low-birth-weight infants. J Perinatol. 2004;24:482 486 35. Simmer K, Rao SC. Early introduction of lipids to parenterallyfed preterm infants. Cochrane Database Syst Rev. 2005;18: CD005256 36. Stephens BE, Walden RV, Gargus RA, et al. First-week protein and energy intakes are associated with 18 month developmental outcomes in extremely low birth weight infants. Pediatrics. 2009; 123:13371343 37. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole K and the National Institutes of Child Health and Human Development Neonatal Research Network. Growth in the neonatal

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intensive care unit inuences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006;117: 12531261 38. Martin CR, Brown YF, Ehrenkranz T, et al and the Extremely Low Gestational Age Newborns Study Investigators. Nutritional practices and growth velocity in the rst month of life in extremely premature infants. Pediatrics. 2009;124:649 657 39. Brans YW, Andrew DS, Carrillo DW, Dutton EP, Menchaca EM, Puleo-Scheppke BA. Tolerance of fat emulsions in very low birth weight neonates. Am J Dis Child. 1988;142:145152 40. Peterson J, Bihain BE, Bengtsson-Olivecrona G, Deckelbaum RJ, Carpentier YA, Olivecrona T. Fatty acid control of lipoprotein lipase: a link between energy metabolism and lipid transport. Proc Natl Acad Sci USA. 1990;87:909 913 41. Cairns PA, Stalker DJ. Carnitine supplementation of parenterally fed neonates. Cochrane Database Syst Rev. 2000;4:CD000950 42. Mirtallo JM, Dasta JF, Kleinschmidt KC, Varon J. State of the art review: intravenous fat emulsions: current applications, safety prole, and clinical implications. Ann Pharmacother. 2010;44:688 700 43. de Meijer VE, Gura KM, Meisel JA, Puder M. Parenteral sh oil monotherapy in the management of patients with parenteral nutrition associated liver disease. Arch Surg. 2010;145:547551

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outcomes in patients with parenteral nutrition-associated liver injury. Ann Surg. 2009;250:395 492 45. Parikh MJ, Dumas G, Silvestri A, Bistrian BR, Driscoll DF. Physical compatibility of neonatal total parenteral nutrient admixtures containing calcium and inorganic phosphate salts. Am J Health Syst Pharm. 2005;62:11771183 46. Hicks W, Hardy G. Phosphate supplementation for hypophosphatemia and parenteral nutrition. Curr Opin Clin Nutr Metabol Care. 2001;4:227233 47. Driscoll M, Driscoll DF. Calculating aluminum content in total parenteral nutrition admixtures. Am J Health Syst Pharm. 2005;62:312315 48. Fewtrell MS, Bishop NJ, Edmonds CJ, Isaacs EB, Lucas A. Aluminum exposure from parenteral nutrition in preterm infants: bone health at 15-year follow-up. Pediatrics. 2009;124:13721379 49. Erikson KM, Thompson K, Aschner J, Aschner M. Manganese neurotoxicity: a focus on the neonate. Pharmacol Ther. 2007;113: 369 377 50. Sherlock R, Chessex P. Shielding parenteral nutrition from light: does the available evidence support a randomized, controlled trial? Pediatrics. 2009;123:1529 1533

NeoReviews Quiz
1. Energy is essential for body maintenance and growth. Knowing the energy balance and its components is important for prescribing parenteral nutrition (PN) in neonates. Of the following, the estimated energy cost in preterm infants is highest for: A. Basal metabolism. B. Body growth. C. Excretory loss. D. Physical activity. E. Temperature regulation. 2. PN solutions may be infused via peripheral or central catheters. Peripheral infusion is usually reserved for short-term nutrition support. The osmolarity of the infusate that can be safely administered via the peripheral route is less than that of the infusate administered via the central route. Of the following, the upper threshold of osmolarity tolerance range for peripherally infused PN solutions is closest to: A. 500 mOsm/L. B. 750 mOsm/L. C. 1,000 mOsm/L. D. 1,250 mOsm/L. E. 1,500 mOsm/L. 3. Previously used intravenous amino acid preparations were based on casein hydrolysates. Current crystalline amino acid preparations have elevated ratios of essential-to-nonessential amino acids. Of the following, the amino acid considered semi-essential in the newborn period and required for the synthesis of glutathione antioxidant is: A. Arginine. B. Cysteine. C. Leucine. D. Tyrosine. E. Valine.
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4. Endogenous glucose production varies with gestational age, and its estimate provides an appropriate starting point for glucose infusion rate in neonatal PN. The upper rate of glucose administration with advancing PN is inuenced by the maximal glucose oxidation capacity of the infant. Of the following, the most appropriate initial rate, daily rate of increase, and maximal rate of glucose infusion in extremely preterm infants receiving PN is: Initial infusion (mg/kg per minute) A. B. C. D. E. 1 1 2 4 4 to to to to to 2 2 4 6 6 Daily increment (mg/kg per minute) 4 4 2 1 1 to to to to to 6 6 4 2 2 Maximal rate (mg/kg per minute) 8 9 10 12 16

5. Lipid emulsions are important components of neonatal PN because they provide an energy source with low osmolarity and high energy content per unit volume. Withholding lipid can lead to essential fatty acid deciency, which can develop in preterm infants within the rst postnatal week and as early as the second day after birth. Of the following, the minimal amount of lipid required to prevent essential fatty acid deciency in preterm infants is: A. B. C. D. E. 0.1 0.5 1.1 1.5 2.1 to to to to to 0.4 1.0 1.4 2.0 2.4 g/kg g/kg g/kg g/kg g/kg per per per per per day. day. day. day. day.

6. The trace elements currently recommended for neonatal PN are zinc, copper, manganese, chromium, selenium, and molybdenum. Although the optimal dose of each trace element remains unconrmed, the goal in nutrition is to prevent deciency of the trace element and avoid its toxicity. Of the following, the most typical manifestation of zinc deciency in neonates is: A. B. C. D. E. Acquired hypothyroidism. Diffuse osteopenia. Hair depigmentation. Hepatic cholestasis. Perianal dermatitis.

7. The trace element preparations for neonatal PN are commercially available as single agents or as combination products. None of the combination products meets the needs of neonates of every gestational or postnatal age or clinical condition, and each may inadvertently provide a specic trace element in amounts in excess of the recommended dose, leading to potential toxicity. Of the following, the neurotoxicity from trace element deposition in the basal ganglia as a special concern for infants receiving parenteral nutrition is most attributed to: A. B. C. D. E. Chromium. Copper. Manganese. Molybdenum. Selenium.

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Parenteral Nutrition in the Neonatal Intensive Care Unit Nahed O. ElHassan and Jeffrey R. Kaiser Neoreviews 2011;12;e130 DOI: 10.1542/neo.12-3-e130

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including high resolution figures, can be found at: http://neoreviews.aappublications.org/content/12/3/e130 This article cites 47 articles, 16 of which you can access for free at: http://neoreviews.aappublications.org/content/12/3/e130#BIBL This article, along with others on similar topics, appears in the following collection(s): Fetus/Newborn Infant http://neoreviews.aappublications.org/cgi/collection/fetus:newborn_i nfant_sub Nutrition http://neoreviews.aappublications.org/cgi/collection/nutrition_sub Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://neoreviews.aappublications.org/site/misc/Permissions.xhtml Information about ordering reprints can be found online: http://neoreviews.aappublications.org/site/misc/reprints.xhtml

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