RD16 Parenteral Nutrition in the NICU 2015 by Jessica McGee, MS, RD, CSP, CNSC, LD

Transcription

1 RD16 Parenteral Nutrition in the NICU 2015 by Jessica McGee, MS, RD, CSP, CNSC, LD Jessica McGee, MS, RD, CSP, LD, CNSC, is a pediatric clinical dietitian and the clinical nutrition manager at Children s National Health System. She specializes in infants and children in the cardiac intensive care unit who require parenteral nutrition, enteral nutrition, ventricular assist devices, and support via extracorporeal membrane oxygenation. The author has declared no relevant conflicts of interest that relate to this educational activity. Summary Parenteral nutrition can be a matter of life or death for infants in the NICU. Infants particularly premature infants often require nutritional support, and parenteral nutrition is used in the first hours or days of life to maximize energy intake while oral or enteral feedings (or a combination of the two) are established. The urgency of initiating PN varies with gestational age and the infant s medical conditions. The urgency in initiating feeding is because of the infant s higher metabolic rate and energy requirement per unit of body weight versus adults, so a delay in instituting parenteral nutrition can have dire consequences. This course will provide the latest evidence-based recommendations to successfully implement parenteral nutrition in the NICU, including determining nutrient needs, explaining how to provide those nutrients, monitoring responses and discussing how to deal with shortages in parenteral products. Goal and Objectives The goal of this continuing education program is to provide current recommendations for optimal nutrition in NICU patients requiring parenteral nutrition. After studying the material presented here, you will be able to: List the indications for parenteral nutrition in the preterm infant Formulate an appropriate parenteral solution containing dextrose, amino acids and lipids with adequate protein and calories required by an infant to support adequate growth Determine appropriate fluid, electrolyte and micronutrient needs of preterm infants receiving parenteral nutrition 1

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4 In many preterm infants, providing parenteral nutrition is crucial within the first 24 hours of life and can be a matter of life or death. Preterm infants often require days to weeks to achieve goal enteral nutrition, time they do not have due to a shortage of stored nutrients and an extremely high metabolic rate. This is why parenteral nutrition, the delivery of nutrients into the circulatory system, is used within the first hours or days of life to maximize caloric intake while oral or enteral feedings (e.g., nasogastric), or a combination of the two methods, are established. This course discusses the assessment and prescription of PN for the preterm infant in the NICU. Given that most fetal nutrient stores are accumulated during the last trimester of pregnancy, premature infants have very minimal caloric reserves. For example, in a preterm infant weighing 1 kg, fat contributes only 1% of total body weight, as compared to a term infant (3.5 kg), whose weight is about 16% fat. 1 The body composition of an infant born at 24 weeks with a birth weight of 500 grams is primarily water and protein, at approximately 90% and 10% respectively, with essentially no fat stores. While preterm infants greater than 28 weeks may contain adequate caloric reserves up to the third day of life, the energy stores of an infant born at less than 28 weeks may not even be sufficient for the first day of life, which can be described as a nutritional emergency in preterm infants less than 28 weeks gestation. 2 In situations where adequate nutrition support cannot be achieved and fat and glycogen stores have been exhausted, infants begin to catabolize protein stores for energy. Infants with a birth weight of less than 1,500 grams catabolize approximately 2% to 3% of protein stores daily without adequate nutrition support. 3 If it is anticipated that an infant will not receive enteral feedings for two to three days, PN should be initiated. 1 In infants with very low birth weight, initiation of parenteral nutrition is recommended within the first 24 hours after birth, which improves glucose tolerance and nitrogen balance. 4 A recent review found evidence that initiation of protein in PN within 24 hours of birth promotes a positive nitrogen balance in preterm infants. These findings may not be clinically pertinent as the review did not show benefit to growth, neurodevelopment, or mortality with early protein 5 (Level A) administration compared to initiation after 24 hours of birth. Premature infants often do not tolerate enteral feedings due to their small stomach capacity and immature gastrointestinal tract. 1 Gastric emptying and intestinal transit times are significantly delayed as compared to the term infant. Organized gut motility does not begin until 32 to 34 weeks gestation. 6 Although it is intuitively understood by most that early aggressive nutrition support for premature infants has a positive impact on outcomes evaluated later in life (such as growth and cognitive function), research confirming long-term outcomes is limited. However, the concept of aggressive PN, or initiating 2 to 3 g/kg/day of protein within hours of birth, is considered by some a misnomer and really should be considered appropriate PN. 2 The impact of early protein and energy intake on neurodevelopment and growth of extremely low birth weight (below 1,000 grams) infants was evaluated and the data revealed that increased protein and energy intakes in the first week of life are...associated with higher Mental Development Index scores and lower likelihood of length growth restrictions at 18 months in extremely low birth weight infants. 7 4

5 Indications for Parenteral Nutrition PN should be initiated immediately for medical conditions where enteral feedings are contraindicated until the medical situation allows for safe initiation of enteral feedings. The majority of cases in the NICU requiring PN support are due to either gastrointestinal malformations or necrotizing enterocolitis. GI malformations include omphalocele, gastroschisis, intestinal atresia, volvulus and Hirschsprung s disease. An omphalocele is a congenital herniation of viscera (e.g., internal organs) into the base of the umbilical cord, with a covering membranous sac. In contrast, gastroschisis is a defect in the abdominal wall resulting from rupture of the amniotic membrane usually accompanied by protrusion of viscera (e.g. internal organs). 8 The surgical repair of these malformations is complex, but essentially the bowel and other organs that are outside of the abdominal cavity are reinserted into the abdominal cavity space and the area is sutured closed. Recovery from omphalocele is generally quicker than gastroschisis because the membranous sac protected the bowel during pregnancy. In gastroschisis, the bowel is often quite dilated and inflamed because of exposure to amniotic fluids. Intestinal atresia is the absence of a normal opening; in other words, the intestinal lumen has a closure where it should be a continuous segment. A volvulus is a twisting of the intestines that causes an obstruction. Hirschsprung s disease, a lack of ganglion cells in the affected segment, is also referred to as congenital megacolon. Intestinal atresia and Hirschsprung s both require surgical repair. 8 Necrotizing enterocolitis is defined as inflammation or necrosis of areas of the intestinal tract. 1 The intestinal wall is invaded by bacteria that can lead to localized infection and inflammation and even perforation of the bowel. Clinical signs of NEC include: 9 Increased abdominal girth (distension) High gastric residual volume Increased emesis Bloody stools NEC is the most prevalent urgent GI medical condition affecting premature infants. 9 NEC is diagnosed via radiological finding of pneumatosis intestinalis, which is caused by bacteria in the bowel that produces gas. 10 Some cases of NEC are classified as medical because a period of bowel rest and administration of antibiotics is sufficient to promote a full recovery. During acute NEC, feedings are frequently held for seven to 21 days to facilitate recovery. Surgical NEC is the term used for cases that require surgical intervention, such as peritoneal drain placement and/or intestinal resection due to bowel perforation. The cause of NEC is unknown and multifactorial. In the past, rapid titration of feedings was implicated as the cause of NEC, but more recently this association has been questioned GI malformations and NEC may require extensive bowel resection, causing intestinal failure, intestinal stricture, SBS (also known as short bowel syndrome) and functional SBS. Intestinal failure results from obstruction, dysmotility, surgical resection, congenital defect, or diseaseassociated loss of absorption and is characterized by the inability to maintain protein-energy, 5

6 fluid, electrolyte or micronutrient balance. 14 Intestinal strictures can occur within three to eight weeks of developing NEC or even months later. 9 These may occur as a result of scar tissue where the bowel was ischemic. 10 SBS is defined as more than 50% anatomical or functional loss of the small intestine. 4 Symptoms of SBS include: 15 Weight loss Growth failure Muscle wasting Diarrhea Steatorrhea Rapid GI transit time Malabsorption Dehydration Electrolyte imbalance Functional SBS is when intestinal dysfunction is associated with malabsorption and the characteristics described above, despite adequate intestinal length (shown in the table below). 16 These conditions constitute the primary causes for long-term PN support. 20 weeks gestation 30 weeks gestation 40 weeks gestation 1 year 5 years 10 years 20 years Age Normal Intestinal Length 16 Mean Intestinal Length 125 cm 200 cm 275 cm 380 cm 450 cm 500 cm 575 cm (ranges 350 to 700 cm) Diaphragmatic hernia often requires PN until surgical repair of the hernia occurs and the stomach and/or intestines are returned to a more anatomically correct place in the abdominal cavity and are functioning (e.g., stooling). Other medical conditions that may warrant the use of PN support include the following: intractable, nonspecific diarrhea; extra corporeal membrane oxygenation (ECMO for cardiac and/or respiratory support, shown below); administration of prostaglandin; and vasopressor support (e.g., dopamine, dobutamine, epinephrine). ECMO and vasopressor support may not be absolute contraindications to enteral feedings; however, many neonatologists are hesitant to enterally feed infants with hemodynamic instability due to risk of bowel ischemia, because these conditions are associated with decreased blood profusion to the gut. 6

7 ECMO for Cardiac and/or Respiratory Support 17 PN is typically administered in lieu of enteral nutrition in patients requiring ECMO or high-dose vasoactives due to concern for gut ischemia and increased risk of developing NEC. However, neither NEC nor intestinal perforation was found in a study using gastric and post-pyloric continuous full-strength EN in infants requiring ECMO. While this study had a small sample size of 27 patients (14 receiving TPN and 13 receiving EN), there was no statistical significance in length of time to achieve goal nutrition (approximately three days and four days, respectively) and the advantages to providing nutrition via the gut outweighed the risks of using PN. The author concluded that EN is not contraindicated while using vasopressor support. 18 Historically, enteral feedings were not administered if an infant was receiving prostaglandin (to treat cardiac defects). A study demonstrated feeding tolerance in 22 of 34 neonates who were fed enterally while receiving prostaglandin, suggesting that it is safe to feed this patient population. 19 There remains a lack of consistency and standard of care regarding use of EN in prostaglandindependent patients, as a recent survey indicated only 56% of healthcare providers in the United States provided feeds while using prostaglandin. 20 Classification of Premature Infants Premature infants are born at less than 37 weeks gestation. Classifications by weight are shown in the table below. Classification of Preterm Infants by Birthweight 4 Low birth weight (LBW) Very low birth weight (VLBW) Extremely low birth weight (ELBW) < 2,500 grams < 1,500 grams < 1,000 grams 7

8 To evaluate in utero growth, it is suggested to plot an infant s birth anthropometrics on the Lubchenco, Fenton, or Olsen growth chart. 4 The recently updated Fenton growth charts now include separate curves for boys and girls reflecting the World Health Organization s growth charts at 50 weeks gestational age and are recommended for use. 21 An infant is appropriate for gestational age if his/her weight plots between the 10th and 90th percentiles, small for gestational age if below the 10th percentile, and large for gestational age if above the 90th percentile. 1,4 One study noted: 1 An SGA infant whose intrauterine weight gain is poor, but whose linear and head growth are between the 10th and 90th percentiles on the intrauterine growth grid, has experienced asymmetric intrauterine growth restriction (IUGR). An SGA infant whose length and occipital frontal circumference are also below the 10th percentile of the standards has symmetric IUGR [which] is apparently more detrimental for later growth and development. Estimating Nutrient Needs Infants have a higher metabolic rate and energy requirement per unit of body weight than children and adults. Energy requirements for premature infants receiving PN are broken down as follows: kcal/kg/day for resting energy expenditure 25 kcal/kg/day for energy storage and growth 10 kcal/kg/day for the thermic effect of feeding 0 to 5 kcal/kg/day for thermoregulation 0 to 5 kcal/kg/day for activity Caloric needs for a full-term infant fed enterally are approximately 100 to 120 kcal/kg/day, whereas those who receive PN require fewer calories (80 to 100 kcal/kg/day) because energy is not needed to cover fecal losses, nor is energy being used for the thermogenic effect of food. 23 The chart below shows the estimated nutrient intake needed for fetal weight gain. Nutrient Intakes to Achieve Fetal Weight Gain 24 Body weight (g) Fetal wt gain (g/day) Fetal wt gain (g/kg/day) Protein (g/kg/day): Parenteral Enteral Energy (kcal/kg/day): Parenteral Enteral The calorie and protein needs of premature infants are even higher than those of full-term newborn infants. The American Academy of Pediatrics recommendations for energy and protein needs of ELBW infants receiving PN are 105 to 115 kcal/kg/day and 3.5 to 4 g pro/kg/day while the needs for VLBW infants are 90 to 100 kcal/kg/day and 3.2 to 3.8 g pro/kg/day. An anabolic

9 state can be accomplished with 60 kcal/kg/day and 2.5 to 3 g pro/kg/day via PN in preterm infants. At least 70 kcal/kg/day of non-protein energy intake via PN is typically required to promote growth. 25 Protein restriction may be warranted in certain instances, such as renal or hepatic failure; however,... protein restriction should be done with caution and consideration should be given to the need for adequate protein to support growth and development. 26 In general, infants who are receiving mechanical ventilator support, sedation and/or paralytic medications have decreased energy needs comparative to the recommended goals sited above. Often meeting 100% of resting energy expenditure is sufficient. The WHO equation listed below provides an estimate for REE. 27 WHO Equation for Estimating REE 27 Males aged birth to 3 years 60.9W 54 Females aged birth to 3 years 61W 51 Note: W = weight in kilograms. This chart provides a starting point for use in patients 0 to 3 years old who are not in a typical healthy state. Metabolic rates vary widely in neonates over time and among neonates on ECMO, where the goal of nutrition support is to minimize catabolism and growth is not expected. 28 An evaluation of nutrition support in neonates on ECMO demonstrated that a surplus in caloric intake does not improve protein catabolism and merely increased CO2 production. 29 The American Society for 30(Level C) Parenteral and Enteral Nutrition recommends the following for neonates on ECMO: Protein up to 3 g/kg/day Energy equal to those of healthy infants (i.e., 100 to 120 kcal/kg/day in a neonate) Initiating enteral nutrition when clinically stable These recommendations are similar to current guidelines from the Academy of Nutrition and Dietetics Pediatric Nutrition Care Manual, which suggests 90 kcal/kg/day and 2 to 3 g pro/kg/day for patients ages approximately 0 to 3 years. 28 Previous studies suggested lower energy needs of 70 to 80 kcal/kg/day while on ECMO, as excess energy intake can lead to increased production of carbon dioxide and will not minimize protein catabolism. 30,31 It is difficult to accurately estimate energy needs as indirect calorimetry and nitrogen balance studies may be inaccurate while on ECMO. 30 However, nitrogen balance studies are widely used to determine if nutrition provided is accurate to promote positive nitrogen balance. It is important to note most recommendations do not specify differences in estimated needs for patients receiving parenteral versus enteral nutrition while on ECMO. Enterally fed premature infants who are not on ECMO and are ELBW require 130 to 150 kcal/kg/day and 3.8 to 4.4 g pro/kg/day. VLBW infants require 110 to 130 kcal/kg/day and 3.4 to 4.2 g pro/kg/day via EN. 25 Premature infants receiving PN require an estimated 90 to 110 kcal/kg/day. Some medical circumstances may require even higher caloric intakes to support adequate growth (e.g., bronchopulmonary dysplasia or congenital heart disease). 9

10 Calorie and Protein Recommendations for Neonates 25,27,28,30 Infants Calories/kg/day Grams Protein/kg/day Premature, enteral 110 to ELBW, enteral 130 to to 4.4 VLBW, enteral 110 to to 4.2 Premature, parenteral 90 to to 3.5 A.S.P.E.N (on ECMO) 100 to Academy of Nutrition & Dietetics (on ECMO) 90 2 to 3 Fluid and Electrolytes It is essential to reevaluate an infant s fluid status daily at minimum, for at least the first week of life. In the first day of life, a full-term infant will require as little as 60 ml/kg/day to meet fluid needs. As the infant matures, fluid needs will increase to 120 to 150 ml/kg/day to allow for increases in renal solute load, fluid losses from stool output, and infant growth. 32 For most preterm infants, fluid needs are 80 to 100 ml/kg/day on Day of Life 1 (DOL1), increasing by 10 to 20 ml/kg/day to 130 to 180 ml/kg/day as the infant matures. 32 The AAP recommends PN provide: to 180 ml/kg/day for ELBW infants 120 to 160 ml/kg/day for VLBW infants Preterm infants have increased insensible water losses due to the immaturity of their skin and respiratory losses. The use of phototherapy increases insensible losses, while thermal blankets and humidified incubators decrease insensible losses. Specific conditions require fluid restriction in infants such as congestive heart failure, congenital heart defects, cerebral edema or renal failure. 1 Close monitoring of electrolyte status is essential. The addition of electrolytes to PN may be deferred until the second day of life in some cases. Potassium is generally added once normal kidney status and good urine output are established, and sodium is often added once diuresis begins. 33 The AAP recommends restricting sodium until the physiological postnatal loss of extracellular fluid is underway. Once sodium levels are below 140 mg/dl, the electrolyte should be added to PN. 25 Daily adjustments to electrolyte intake are often necessary. Electrolyte requirements of preterm and full-term infants are generally similar, with the exception of calcium and phosphorus

11 Chloride Daily Electrolyte Requirements for Pediatric Patients 34 Electrolyte Preterm Neonates Infants/Children Sodium 2 to 5 meq/kg 2 to 5 meq/kg Potassium 2 to 4 meq/kg 2 to 4 meq/kg Calcium 2 to 4 meq/kg 0.5 to 4 meq/kg Phosphorus 1 to 2 mmol/kg 0.5 to 2 mmol/kg Magnesium 0.3 to 0.5 meq/kg 0.3 to 0.5 meq/kg Acetate As needed to maintain acid- As needed to maintain acid- base balance As needed to maintain acidbase balance base balance As needed to maintain acidbase balance Access for Administering PN PN can be administered through a peripheral vein as peripheral parenteral nutrition. PPN requires a relatively large volume to allow for adequate administration of nutrients. In the critically ill infant, nutrient requirements often cannot be met with PPN due to fluid restriction. When providing PPN, recommendations are to limit dextrose concentration to 10% to 12.5% and limit final osmolality to 900 mosm/l in an effort to minimize risk of phlebitis and infiltration. Total parenteral nutrition requires central vein access and allows for administration of a solution with a higher osmolality above 900 mosm/l. 34 X-ray confirmation of central-line placement is essential prior to administration of a solution with a high osmolality. Dextrose concentration of PN solution administered via a central line is generally limited to a maximum of 25% as there s an increased risk of thrombosis using higher concentrations. 35 Venous access is not defined by the initial point of entry, but by the position of the catheter tip. With central lines, the catheter tip terminates in the superior vena cava or the right atrium of the heart. 34 Examples of CVL that are found in infants include umbilical venous catheters, nontunneled lines and tunneled lines. UVC are generally placed after birth and are removed within two weeks due to increased risk of infection 36 and increased risk of thrombosis. 36,37 Non-tunneled lines include femoral, jugular, subclavian and peripherally/percutaneously inserted central catheters. PICC lines are generally placed when a long-term IV access is needed, and duration may vary from several days to months. PICC lines may be central or peripheral, depending on the placement of the catheter tip. If the PICC line terminates in the superior vena cava it is considered central, and termination in other vessels needs to be individually evaluated to define the maximum concentration of dextrose that can be safely infused. A Broviac line is the tunneled line typically used in pediatric patients. Broviac lines are often placed when an infant is expected to be discharged on home PN support, as with SBS patients

12 Macronutrients The table below provides an overview of how to initiate and advance macronutrients in PN per A.S.P.E.N recommendations. Recommendations for Initiation and Advancement of Parenteral Nutrition 34 Infants (< 1 yr) Initiation Advanced By Goals Preterm Term Preterm Term Preterm Term Protein 3 to to 3 N/A N/A 3 to to 3 (g/kg/day) CHO (mg/kg/min) 6 to 8 6 to to to 14 (Max to 14 (Max 14 Fat (g/kg/day) to 18) 0.5 to to to to 1 3 (Max 0.15 g/kg/hr) to 18) 2.5 to 3 (Max 0.15 g/kg/hr) Some NICUs are now using stock amino acid and dextrose solution (e.g., starter PN ) to facilitate the timely initiation of PN, which may be started in the delivery room or on the first day of life. The composition of this type of PN varies from 5% to 10% amino acids and 2% to 5% dextrose. Some institutions have added electrolytes such as calcium gluconate. Contraindications for the use of stock PN may include patients with possible metabolic disorders or renal or hepatic failure. 1,39 On DOL 1, the following is recommended: 2 80 to 100 ml/kg/day of commercially available PN 2.4 to 2.7 g/100 ml of protein Dextrose 10% 2 g lipids/kg/day Within the first 24 hours in preterm infants, the goal is at least 2 g protein/kg/day and 60 to 80 kcal/kg/day Carbohydrate via PN is in the form of dextrose monohydrate and provides 3.4 calories per gram. The glucose utilization rates of preterm infants can be up to twice the amount of term infants. 22 Glucose infusion rates should be: 22,34 Initiated at 6 to 8 mg/kg/min for preterm infants Advanced by approximately 1 to 2 mg/kg/min per day to goal of 10 to 14 mg/kg/min for preterm infants Initiated at 6 to 8 mg/kg/min for term infants Advanced by 3.5 mg/kg/min per day to goal of 10 to 14 mg/kg/min for term infants GIR should be restricted to no more than 14 to 18 mg/kg/min as maximum glucose oxidation typically occurs at this point and excess glucose increases fat synthesis, which may increase production of CO2, potentially causing respiratory distress

13 Other potential adverse effects of an elevated GIR include hyperglycemia, inflammatory injuries, and infiltration of fat to the heart and liver, leading to steatosis. 22 While insulin can be used to treat hyperglycemia, recent evidence indicates there are risks that include inhibited protein synthesis in preterm infants, insulin adhering to IV tubing and causing inconsistent delivery and fluctuations in blood glucose levels, an increased risk of hypoglycemia and decreased linear 1,25,40(Level A) growth. Protein is administered as a crystalline amino acid solution, which provides 4 calories per gram. TrophAmine, Aminosyn PF, and Premasol are amino acid solutions most appropriate for use in infants as they are designed to mimic the amino acid concentration of breast milk. These contain higher concentrations of essential amino acids, including tyrosine and histidine, as well as nonessential amino acids. Additionally, the lower ph of these solutions allow for a greater amount of calcium and phosphorus to be added in PN. 34 One study comparing Trophamine and Aminosyn PF revealed a possible decrease in PN-associated liver disease with the use of Trophamine compared to patients receiving Aminosyn PF who had a higher incidence of PNassociated liver disease and higher levels of conjugated bilirubin. 41 For more details regarding adequate protein for growth in PN, refer to the Estimating Nutrient Needs section above. Fat. The fat source in PN is intralipid, also known as intravenous fat emulsion, which provides 10 calories per gram. IVFE in the U.S. is composed of soybean and/or safflower oil and provides essential fatty acids. IVFE is available in 10% (1.1 kcal/ml) and 20% (2 kcal/ml) concentrations to be used in 2-in-1 mixtures and 30% concentrations available for 3-in-1 solutions. 34,36 In pediatric patients, the 20% solution is commonly used to provide adequate energy from fat in a smaller volume. 34 Another potential benefit to providing a 20% concentration was found in a study stating: 33 The 10% solution has a higher phospholipid/triglyceride weight ratio than the 20% solution, and this higher ratio may affect the activity of lipoprotein lipase, the primary enzyme for lipid clearance, resulting in higher triglycerides and other plasma lipids in infants. In addition to being calorically dense, another benefit to IVFE is its osmolality is the same as plasma, thus there is no aggravation to the veins. Lipids should be initiated at 0.5 to 1 g/kg/day and advanced by 0.5 to 1 g/kg/day to a maximum of 3 g/kg/day in preterm infants according to the AAP and A.S.P.E.N. recommendations. 25,34 For infants weighing less than 1 kg, it may be beneficial to initiate lipids at 2.0 g/kg/day and advance by 0.5 to 1.0 g/kg/day to a goal of 3.0 g/kg/day. 33 Approximately 25% to 40% of non-protein calories should be from IVFE in PN. 25 One study states the following regarding IVFE: 2 The optimal lipid emulsion needs to provide essential fatty acids, maintain longchain polyunsaturated fatty acid (PUFA) levels and immune function, and reduce lipid peroxidation. IVFE should not be infused faster than 0.15 g/kg/hour in term infants and 0.17 g/kg/hour in preterm infants as this may negatively impact pulmonary and immune function, as well as 13

14 increase risk for kernicterus in infants with hyperbilirubinemia. 34,37 In septic patients, limiting IVFE infusion to less than 0.08 g/kg/hour is recommended. 37 To monitor fat tolerance, consider checking serum triglyceride levels twice weekly with a goal of less than 200 mg/dl. 2,25 To prevent essential fatty acid deficiency, infants require a minimum of 0.5 to 1 g/kg/day of lipids. 34 EFAD can develop in premature infants during the first week of life and as early as the second day of life. 33 Providing at least 2% to 4.5% of total calories as linoleic acid and 0.25% to 0.5% as linolenic acid is likely sufficient to prevent EFAD. 37,42 Signs and symptoms of EFAD include dry skin, alopecia, thrombocytopenia, impaired wound healing, increased risk of bacterial infections and poor growth. 37,42 EFAD was previously diagnosed if a patient s triene:tetraene ratio was greater than or equal to New diagnostic criteria according to Mayo Medical Laboratories is a triene:tetraene ratio greater than in infants up to 1 month old and greater than 0.05 after 1 month of age. 43 Soybean and safflower oil-based lipid emulsions contain pro-inflammatory and immunosuppressive omega-6 fatty acids. IVFE high in omega-6 fatty acids may contribute to and/or accelerate the development of PN-associated liver disease. Limiting IVFE in PN to 1 g/kg/day may inhibit or slow the progression of PNALD. 25 Restricting IVFE causes a calorie deficit that must be met; usually the additional calories are provided as glucose, resulting in a higher GIR. In recent years, several studies have evaluated the benefits of providing an omega-3 fish oilbased fat in PN known as Omegaven. This type of fat is thought to protect the liver due to the following: 44,45 Contains anti-inflammatory properties Aids lipid metabolism by decreasing de novo lipogenesis and promoting beta-oxidation May regulate tumor necrosis factor-alpha to protect cells Free from phytosterols, which are present in soy-based lipids that may negatively impact biliary secretion A study evaluating the safety and efficacy of using Omegaven in infants with cholestasis revealed that administering 1 g/kg/day is effective in reversing cholestasis, and none of the subjects developed EFAD. 46 Another study compared the use of soybean oil-based IVFE versus Omegaven. The results were as follows: 47 Among survivors not transplanted during PN, cholestasis reversed while receiving PN in 19 of 38 patients in the fish oil cohort versus 2 of 36 patients in the soybean oil cohort Subjects receiving fish oil-based [IVFE] experienced reversal of cholestasis 6 times faster (95% CI: ) than those receiving soybean oil-based [IVFE]. The provision of fish oil-based [IVFE] was not associated with hypertriglyceridemia, coagulopathy, or essential fatty acid deficiency. In a recent study, five preterm infants with SBS and PNALD were provided Omegaven and ClinOleic (IV fat containing soy and olive oil) in a 1:1 ratio with total fat intake of 2 g/kg/day; however, total fat was limited to 1 g/kg/day (0.5 g/kg/day from each type of fat) for patients in a septic state. Omegaven was initiated at 0.2 g/kg/day and advanced by 14

15 0.2 g/kg/day to the goal of 1 g/kg/day. The direct bilirubin levels decreased to normal in all five patients while receiving this fat ratio. 48 Although this product is available in other countries, Omegaven can only be prescribed in the U.S. via FDA compassionate approval (in addition to obtaining your hospital s Institutional Review Board approval) if the patient meets the criteria. Omegaven is not currently indicated for the prevention of PN-associated cholestasis in patients; however, Boston Children s Hospital evaluated this concept in a clinical trial, although results are not yet available. 49 The cost and logistics of obtaining the product remain a challenge. Further information on the steps necessary to obtain this product can be found here. Vitamins, Minerals and Trace Elements Vitamin needs of preterm infants are likely different than term infants due to immaturity of vitamin absorption, excretion, enterohepatic circulation, and renal tubular reabsorption mechanisms. Recommended vitamin doses may be underestimated for larger infants or overestimated in smaller infants. 37 PN vitamin dosing in premature infants often provides inadequate amounts of vitamins A and D, as well as excessive amounts of many B vitamins. The optimal combination of each vitamin is not available for infants of varying gestational age and individual vitamins are not available as ingredients for PN. 25 Available trace element combination products do not adequately meet the needs of preterm neonates either. Many of the combination products provide as much as 5 times the recommended amounts of manganese, which can lead to neurotoxicity in infants and may prompt development of PNALD. 32,37 As a result of these potential consequences, individual trace elements are recommended rather than combined products in the neonatal population. 32 Available minerals include zinc, copper, manganese, selenium, chromium, molybdenum, iron and iodine. 32,37 In VLBW infants, zinc, copper, selenium and iodine are required in PN within the first few days of life. 50 The charts below show the recommended vitamins and mineral doses for infants. Recommendations for Pediatric Multiple Vitamins* 25,34 Manufacturer NAG-AMA** Weight (kg) Daily Dose (ml) Weight (kg) Daily Dose <1 1.5 <2.5 2 ml/kg*** 1 to >2.5 5 ml >3 5 * Pediatric multiple vitamin formulation (5 ml): vit A 2300 IU; vit D 400 IU; vit E 7 IU; vit K 200 mcg; vit C 80 mg; vit B mg vit B mg; niacin 17 mg; pantothenic acid 5 mg; vit B-6 1 mg; vit B-12 1 mcg; biotin 20 mcg; folic acid 140 mcg. **Nutrition Advisory Group-American Medical Association ***The AAP recommends 40% per kg of the total 5mL volume for premature infants. Example: 40% of 5 ml = 2mL; 2 ml x 2kg = 4 ml/day dose 15

16 Trace Element Daily Requirements 34,50 Trace Element Preterm Neonates < 3 kg (mcg/kg/day) Term Neonates 3 to 10 kg (mcg/kg/day) Zinc to 250 Copper 20* 20 Manganese 1 1 Chromium 0.05 to Selenium 1.5 to 2* 2 *In VLBW and ELBW infants, 40 mcg/kg/day of copper is recommended and 5 to 7 mcg/kg/day of selenium Zinc is a component of multiple enzymes required for cell growth and development. 32,34 Zinc deficiency can cause failure to thrive, diarrhea and skin rash, and potentially reduce neurodevelopment. 32,50 All premature infants requiring PN should be supplemented with zinc, even in short-term PN of approximately 1 to 2 weeks. 25 Patients with the following medical conditions benefit from additional zinc intake: 34 High output renal failure High output fistula Large volume stool or ostomy losses Wounds Copper is an essential component of several enzymes and needed to synthesize antioxidants. 25,34 The recommended dose of 20 mcg/kg/day in neonates is sufficient to prevent deficiency; however, 40 mcg/kg/day is recommended in PN for a net retention of 30 mcg/kg/day in VLBW and ELBW infants. 34,50 Zinc supplementation can interfere with the absorption of copper, leading to deficiency. 37,50 Clinical manifestations of copper deficiency include: 32,34 Hypochromic anemia that does not improve with iron therapy Neutropenia Thrombocytopenia Osteoporosis Poor weight gain Infants with high biliary losses, such as those with a jejunostomy, require additional copper intake of 10 to 15 mcg/kg/day. Because copper is excreted via bile and can accumulate to toxic levels in infants with cholestasis, it was historically withheld from PN in this population. However, evidence of copper deficiencies prompted updated recommendations to reduce supplementation by 50% (i.e., 10 mcg/kg/day), monitor ceruloplasmin and serum copper levels monthly, and adjust supplementation as needed. 34 Manganese is needed for several enzymes, important for bone formation, and provides protection from free radicals. A minimal number of cases of manganese deficiency are reported, but clinical signs include scaly dermatitis, short stature and poor bone density. 50 Manganese toxicity can cause manganese deposits in the basal ganglia and may lead to PNALD

17 A maximum dose of 1 mcg/kg/day is recommended according to ESPEN/ESPGHAN and A.S.P.E.N guidelines. 34,50 Manganese should be removed from PN in patients with cholestasis and levels should be monitored and adjusted accordingly. 25,34,50 Selenium is a component of the antioxidant enzyme glutathione peroxidase and required for thyroid metabolism. Selenium deficiency is rare and associated with cardiomyopathy, bronchopulmonary dysplasia, muscle weakness, loss of hair, loss of skin pigmentation and erythrocyte macrocytosis. 50 The antioxidant glutathione peroxidase is involved in protecting cell membranes from peroxidase damage (free radicals) through detoxification of peroxides and free radicals. 51 In infants receiving PN longer than a month, supplementation with selenium is recommended. 34 In VLBW infants, selenium insufficiency may develop in the first weeks of life, as evidenced by decreased plasma selenium levels in several studies. therefore higher selenium doses of 5 to 7 mcg/kg/day in PN have been recommended for ELBW and VLBW infants. 50 Decreasing or removing selenium in PN for patients with renal dysfunction is recommended. 25,36 Chromium enhances the action of insulin, thus improving glucose tolerance, and is involved in glucose, protein and lipid metabolism. 34,50 Chromium deficiency has not been reported in term or preterm infants. 50 Chromium should be decreased or removed from PN in patients with renal dysfunction. 34 Chromium is not needed for short-term PN and as it is commonly a contaminant in PN. Supplemental chromium may not be necessary for long-term PN either. 50 Molybdenum deficiency has not been reported in infants or children, thus supplementation is recommended only in patients requiring PN for longer than a month. 50 If needed, dosage recommendations range from 0.25 to 1 mcg/kg/day in premature infants. 32,50 Iodine is a component of thyroid hormones and necessary for adequate metabolism, growth, development and temperature control. Iodine deficiency leads to: 50 Goiter Cretinism Hypothyroidism Substandard growth Increased mortality in infants Iodine is often omitted from PN due to absorption of topical iodine-containing disinfectants and detergents. 34 However, several hospitals have discontinued use of iodine-containing disinfectants due to a risk of excessive iodine intake. Thus, current recommendations for preterm infants are to provide 1 mcg/kg/day of iodine if iodine-containing antiseptics are used or provide 10 mcg/kg/day in PN if such antiseptics are not used. 50 Iron deficiency, for which preterm infants are at a high risk of developing, is a microcytic hypochromic anemia. Iron deficiency can negatively impact brain development in infants, but can also increase infection risk, impede growth, and increase risk for retinopathy of prematurity if excessive amounts are given. Iron should not be added to PN mixtures containing lipids as there is a risk of lipid destabilization and peroxidation. 17

18 It is not recommend to routinely add iron to PN, but in premature infants requiring long-term PN who are unable to tolerate enteral iron, a dose of 0.2 to 0.25 mg/kg/day is recommended. 50 Shortterm studies demonstrated tolerance of 1 mg iron/kg/day in patients receiving erythropoietin. Iron supplementation is not needed in VLBW infants receiving at least 180 ml of packed cells. 37 Monitoring iron status is imperative with iron supplementation as there is a risk of iron overload. 26 Calcium and Phosphorus Premature infants have an increased risk of developing osteopenia of prematurity for several reasons: 52 Approximately 80% of bone mineralization occurs in the third trimester Goal for enteral nutrition is not established quickly in most preterm infants Inability to provide optimal calcium and phosphorus via PN Use of medications like diuretics and corticosteroids that increase mineral excretion Aluminum contamination of PN Immobility of infants who are critically ill Potential for vitamin D deficiency When maximizing calcium and phosphorus in PN, there is a risk of precipitation. It is essential to collaborate with a pharmacist to review solubility curves to identify safe yet maximum levels of calcium and phosphorus that can be added to the PN mixture. 33 The use of L-cysteine, compounding protocols and filters can help minimize risk of precipitation. 37 Calcium/phosphorus ratios under 1 to 1 by weight (0.8 to 1 by molar ratio) and alternating daily infusions of calcium and phosphorus are not recommended. Calcium supplementation is usually provided as calcium gluconate and phosphorus in the form of sodium phosphate or potassium phosphate. Maximal retention can be accomplished when providing between 1.3 to 1 and 1.7 to 1 calcium/phosphorus by weight or 1.1 to 1.3 to 1 by molar ratio. 33 The chart below shows the calcium, phosphorus and magnesium recommendations for premature and term infants. 18

19 Preterm Infants Term Infants Calcium, Phosphorus and Magnesium Recommendations for PN 25,37,53 Old AAP Recommendations for Preterm Infants Minerals Initial Dose Goal Calcium 25 to 40 mg/kg/day 65 to 100 mg/kg/day Phosphorus 18 to 30 mg/kg/day 50 to 80 mg/kg/day Magnesium 0 to 3 mg/kg/day 7 to 10 mg/kg/day Calcium 20 to 40 mg/kg/day Phosphorus 30 to 45 mg/kg/day Magnesium 3 to 12.5 mg/kg/day Calcium 60 to 80 mg/kg/day Phosphorus 45 to 60 mg/kg/day Magnesium 4.3 to 7.2 mg/kg/day In premature infants, recommendations for initiation and goals (pending laboratory values) are listed above and are higher than previous AAP recommendations. The requirements of calcium and phosphorus in term infants are less than those of preterm infants. For patients at increased risk for metabolic bone disease A.S.P.E.N guidelines recommend providing higher doses of calcium and phosphorus in PN, although exact dosages were not provided (Level C) and reducing 53(Level A) aluminum content in PN to less than 5 mcg/kg/day. For the prevention and treatment of osteopenia of prematurity in the NICU at Children s National Health System, a protocol is used. Part of the preventive strategies for infants at risk for osteopenia receiving PN include: Monitoring weekly alkaline phosphatase levels Obtaining X-rays to monitor for signs of osteopenia when warranted Limiting use of diuretics and steroids as feasible Maximizing calcium (ionized calcium of 1.4) and phosphorus in PN with use of L- cysteine If the ALP level is elevated above 600 IU/L or bone abnormalities are seen on X-ray, additional labs are drawn including 25-hydroxy vitamin D level, urine calcium, and intact PTH. Aspects of the treatment for osteopenia include additional calcium, phosphorus, vitamin D, lab monitoring, and an osteopenia physical activity protocol per the occupational therapist. 19

20 PN Additives: Heparin, Carnitine and Cysteine Addition of heparin to PN solutions reduces the formation of a fibrin sheath around the catheter, may reduce phlebitis and increases the duration of catheter patency. 33 Heparin also stimulates the release of lipoprotein lipase, which may improve lipid clearance. It is recommended to add 0.25 to 1.0 units heparin/ml of PN solution. There is an increased risk of anticoagulation with the higher doses of heparin. 33 Carnitine is needed to transport long-chain fatty acids into the mitochondria where they are metabolized via beta oxidation. 32,34 Carnitine levels are often low in premature infants and those most at risk for deficiency include infants who are VLBW, less than 30 weeks gestation, or with liver or renal dysfunction. 25,37 A recent review indicates routine carnitine supplementation via PN is not supported as improvements in growth, fat utilization, or ketogenesis were not evident. 54(Level A) Despite these findings, in many institutions it remains common practice to supplement carnitine in long-term PN patients at a dose of 2 to 10 mg/kg/day. 25,33 Cysteine, a conditionally essential amino acid in the newborn, is routinely added to PN solutions. It is a precursor to the antioxidant glutathione and synthesized endogenously from methionine in adults and children. 32,34,37 Cysteine supplementation may not be required after the neonatal period when 120 mg methionine/kg/day is provided. By DOL 3 in term infants and DOL 9 in preterm infants, cystathionase activity increases to 70% that of adults. 37 Current practice suggests supplementation with L-cysteine hydrochloride for the first year of life, although practice varies widely. 26 Cysteine improves the solubility of calcium and phosphorus in PN by lowering the ph and typical dosing is 30 to 40 mg per gram of protein. 32 A recent review evaluated the routine supplementation of cysteine to PN and its impact on growth in infants. Their conclusion does not support adding cysteine to PN as stated 55(Level A) below: Available evidence from RCTs shows that routine short-term cysteine chloride supplementation of cysteine-free PN in preterm infants improves nitrogen balance. However, there is insufficient evidence to assess the risks of cysteine supplementation, especially regarding metabolic acidosis, which has been reported during the first two weeks of cysteine chloride administration. Available evidence from a large RCT trial does not support routine N-acetylcysteine supplementation of cysteine-containing PN in extremely low birth weight infants. Complications of PN A summary of the various short-term and long-term complications of PN from the A.S.P.E.N Nutrition Support Pediatric Core Curriculum is shown below. 34 Short-term potential adverse effects of PN may include: Infection Hyperglycemia Electrolyte abnormalities 20

21 Disturbance of acid-base balance Hypertriglyceridemia Bacterial translocation Compromised gut integrity Long-term PN adverse effects may include: 34 Infection PN-associated cholestasis Metabolic complications Disturbance of acid-base balance Osteopenia Risk of vitamin/mineral deficiency or toxicity Bacterial translocation Nosocomial infections appear to result either from improper care of the catheter and/or frequent use of the catheter for purposes other than delivery of nutrients (e.g., blood draws, medication administration). 34 Monitoring Suggested monitoring of various laboratory tests for pediatric patients receiving PN is summarized in the table below. 21