Parenteral nutrition in infants and children

INTRODUCTION — Safe, long-term parenteral nutrition (PN) was first described in infants in 1972 [1]. Since that time, it has contributed to the survival of many children. Soon after the development of PN, however, it became clear that serious problems were commonly associated with its use. Changes in the gastrointestinal (GI) luminal contents, GI function, metabolic abnormalities, cholestasis, liver compromise, and blood stream infections were reported. These problems dampened enthusiasm and led, in some instances, to recommendations against its use [2]. The indication for pediatric PN is limited to those children whose GI tract is inadequate to support normal growth and development.

Enteral nutrition should be used instead of or in addition to PN whenever possible. PN should be used only when it is not possible to meet nutritional requirements via the GI tract for a prolonged time. Enteral nutrition has several physiologic advantages as compared with PN and generally has fewer complications. Indications and management of enteral nutrition for infants and children are discussed in a separate topic review. (See "Overview of enteral nutrition in infants and children".)

Premature infants have a number of unique characteristics that affect the implementation and safety of PN. These considerations are discussed in a separate topic review. (See "Parenteral nutrition in premature infants".)

PHYSIOLOGY — PN is inherently nonphysiologic because nutrients are delivered directly to the systemic circulation, bypassing the gastrointestinal (GI) tract and the portal circulation, which are the usual routes of nutrient entry. Nutrients delivered intravenously through PN avoid the "first pass" effect of passage through the liver. The targets for nutrient intake administered via PN are designed to approximate the nutrient content that reaches the systemic circulation in enterally fed patients.

The effect of PN on physiology can be placed into three broad categories:

●Absence of enteral nutrients – Consequences of bypassing the GI tract and portal system, including lack of the direct effects of enteral nutrients on enterocytes, and loss of the "first pass" effect.

●Missing nutrients – Sequelae from missing or deficient nutrients in the systemic circulation.

●Abnormal or imbalanced nutrients – The effect of nutrients not ordinarily found in the systemic circulation or, if present, in differing amounts or ratios.

Knowledge of which nutrients should be included or omitted in PN, and the optimal nutrient ratios, is based largely on trial and error. Since PN is most frequently used in severely ill and/or malnourished patients, it is not easy to distinguish among the effects of PN, the underlying disease, and malnutrition. As an example, it is well known that malnutrition results in profound changes in the GI tract, with thinning of the mucosa, blunting of villi, and increased translocation. From animal studies, we know that many of these same changes are seen in parenterally fed animals that are nutritionally replete, indicating that some of these effects are due to under-use of the GI tract, rather than direct effects of the PN itself [3].

One of the most profound effects of not using the GI tract is that infants do not learn how to eat. Infants learn coordinated chewing and swallowing foods of different textures and tastes during certain "critical periods" of their development [4]. Infants who are not fed by mouth during these critical periods may fail to develop normal interest in food and the ability to eat. Moreover, their parents may fail to develop normal responses to the infant's cues for feeding. It may take years to overcome the oral hypersensitivity and food aversion that results from a lack of feeding experience during the critical periods. This often leads to a prolonged transition from parenteral feeding to full oral feeds, which can be frustrating to parents and caregivers.

When the enteral route is bypassed, so are the physiologic consequences of eating. The ingestion of food leads to a surge of hormones, neurotransmitters, and enzymes. These mediators result in coordinated GI motility. Little is known about the alterations in GI motility that are associated with PN. Animal data suggest that motility of the stomach, duodenum, and gallbladder is reduced during PN. The decrease in gallbladder motility may in part explain the increase in gallstones that is associated with PN. Interestingly, PN does not affect motility in the jejunum in dogs [5].

The adverse effects of lack of enteral nutrition appear to be mediated in part by glutamine deficiency, although the clinical implications of this observation remain unclear. Glutamine is the major fuel of the enterocyte. The intestinal cell derives glutamine both from the lumen of the GI tract and from the blood stream. If the GI tract is not used, there is no glutamine in the intestinal lumen for the enterocytes to absorb directly. Since standard PN solution has limited glutamine, the enterocyte may be severely depleted of its main fuel source. In animal models of enterocolitis or intestinal resection, supplemental glutamine promotes recovery [6]. However, clinical studies in humans have generally failed to show benefits of enteral or parenteral glutamine supplementation. As an example, a study in which glutamine was supplied both intravenously and intraluminally to very ill adults with multiorgan failure in an intensive care unit setting found no advantage to added glutamine, and mortality was higher in the glutamine supplemented group [7]. (See "Management of short bowel syndrome in children", section on 'Pharmacologic therapy' and "Nutrition support in intubated critically ill adult patients: Enteral nutrition", section on 'Extra supplements of no proven benefit'.)

INITIATING PARENTERAL NUTRITION

Indications and contraindications — If the gastrointestinal (GI) tract is partially functional, the enteral route should be used even for a fraction of the required nutrients [8]. Rarely, the GI tract cannot be accessed and all nutrients must be delivered via the parenteral route; this is known as total parenteral nutrition (TPN). TPN is the last resort when oral intake, enteral feeding, and the combination of partial PN and enteral feeds are not possible. Examples of conditions in which PN or TPN is indicated are given in the table (table 1). (See "Overview of enteral nutrition in infants and children".)

●Infants and children – PN is indicated for infants and children who are unable to be fed enterally if nutritional support is expected to be required for seven days or more. Well-nourished children or adolescents tolerate up to seven days without nutrition support [9]. Patients in this age group who are unable to eat or tolerate enteral feeds should be evaluated within three days to ensure that PN is initiated within four to five days. Adults can tolerate 7 to 10 days without nutrition support [10]. There is no evidence to support the use of PN to "prepare" a patient for surgery unless the patient is severely malnourished [2].

PN should not be used for short periods of time, because the risks can outweigh benefits [11]. The appropriate time for initiating PN should be individualized and depends on individual patient characteristics, including age, nutritional status, underlying disease process, and expectations for future nutritional needs. However, in one randomized trial in critically ill children, relatively late PN initiation (eg, one week after intensive care unit admission) was associated with possible benefits (shorter length of stay in intensive care unit, reduced risk of new infections), even in a subgroup of critically ill children who were undernourished [11,12]. Moreover, in long-term follow-up four years later, children with late PN initiation performed as well or better on measures of neurocognitive function compared with children who started PN earlier in the stay [13].

●Neonates and premature infants – PN is typically initiated earlier for premature infants and term neonates. If it is clear that the infant will not tolerate enteral feeds, then PN usually should be initiated within the first two days of life. These infants have limited nutritional reserves and are able to tolerate starvation or semistarvation for only one to three days.

For preterm infants <1500 g birth weight, PN is generally initiated in the first day of life. Timing and composition of PN and enteral feeds for premature infants are discussed separately. (See "Parenteral nutrition in premature infants", section on 'Phases of parenteral nutrition' and "Approach to enteral nutrition in the premature infant".)

However, for critically ill term neonates, the optimal timing of PN initiation remains unclear. As an example, early versus late initiation of PN was evaluated in a randomized trial in critically ill, term neonates admitted to the intensive care unit [14]. The late initiation group had fewer infections and a greater likelihood of live discharge from the intensive care unit but also a significant increase in episodes of hypoglycemia. Thus, the relative benefits and risks of early versus late initiation of PN has not been established for this group of patients [15].

When extra caution should be used — PN, whether provided peripherally or centrally, should only be used in patients who are hemodynamically stable and are able to tolerate the necessary fluid. PN should be used with particular caution for children with electrolyte imbalance, renal or hepatic compromise, metabolic acidosis, or alkalosis. Acid-base and electrolyte abnormalities should be corrected prior to starting PN, or corrected by infusions through a separate intravenous line. PN should not be used to correct metabolic imbalances.

Children and adolescents undergoing treatment for cancers may or may not be malnourished. Their nutritional status plays an important role in deciding on the nutritional support necessary. PN is no more effective than enteral nutrition in children undergoing chemotherapy, as suggested by a meta-analysis [16]. No meta-analysis is available for malnourished children undergoing treatment, but several reviews in adults raise concerns about the use of PN in patients undergoing chemotherapy, and the American Gastroenterological Association advises against its use [2]. No studies have identified individual nutrients that have a positive effect on outcomes. These studies reinforce the concept that PN should only be used when other methods of nutrition support are not possible or have failed. If PN is deemed necessary in children and adolescents undergoing treatment for cancer, then general principles should be followed for the initiation and maintenance of PN in malnourished and non-malnourished patients, as outlined below.

Central and peripheral venous access — PN can be administered through a peripheral or a central vein. Central venous access is defined as a catheter whose distal tip lies in the distal vena cava or right atrium [17]. To avoid cardiac tamponade, there is some evidence that the catheter tip should lie outside of the pericardial sac, especially in premature babies [18]. Any IV not fitting this definition is considered peripheral. Generally, the choice of central versus peripheral venous access depends on the anticipated duration of the nutrition therapy.

●Osmolarity considerations – The maximum osmolarity that can be delivered via a peripheral vein is 900 mOsm/L, and this constraint limits the amount of nutrients that can be provided by a peripheral IV.

The osmolarity of a PN solution can be determined with the following equation [19]:

Given this osmolarity restriction, it is usually impossible to supply all of the required nutrients with peripheral PN, and central venous access will be required to meet the child's full nutritional needs. Therefore, if an infant or child is likely to need parenteral nutritional support for more than two weeks, a central venous catheter should be placed to meet the nutrition needs of the patient.

●Types of catheters – A variety of catheters are used for PN which differ in how they are inserted, how they are fixed in place, and where they terminate. These characteristics determine for what purposes and for how long they can be used. For all catheters that are intended to end centrally, imaging is required to confirm tip position. The main types of catheters and their characteristics are:

•Percutaneous nontunneled central catheters – These catheters are usually inserted via the subclavian, jugular, or femoral veins. This type of catheter is most appropriate for short-term PN of one to two weeks. These catheters are easily removed and can be replaced over a guide wire; however, they are associated with a high infection rate especially those placed via the femoral vein.

•Tunneled cuffed central catheters – These catheters are placed surgically. The catheter is tunneled subcutaneously before it enters the vein, commonly the jugular or cephalic veins. This type of catheter is appropriate for long-term PN including home PN. It has a lower infection rate than the nontunneled catheters. The major drawback of this type of catheter is that a surgical procedure is required both for placement and for removal.

•Peripherally inserted central catheters (PICC) – These can be placed via any peripheral vein but are typically placed via the antecubital vein. PICC lines are appropriate for medium-term use, up to several months. With special care they can be used for home PN. The major advantage of PICC lines is the ease with which they can be inserted. PICC placement can occur anywhere in a hospital, from emergency room to the patient's bedside with low risk. Because of errors in estimates of insertion length, it is particularly important to confirm central positioning of a PICC line.

•Implanted ports – These are used only for long-term therapies including PN. They may be of benefit when adequacy of catheter care is in question or when body image is important. It also may be helpful if intermittent PN is planned. The subcutaneous port is accessed via a percutaneous needle that can remain in place for hours or up to a week. When not being used, the needle is removed, leaving nothing externally visible. Implanted ports have a low rate of infection, but if an infection does develop, it is difficult to clear, and treatment may require removal of the port. Placement and removal of an implanted port require surgical or interventional radiology procedures.

•Peripheral catheters – Peripheral catheters are only appropriate for infusions of PN with osmolarity of up to 900 mOsm/L, and they need to be replaced frequently. These limitations mean that they can be used only for PN in conjunction with partial enteral feeds, and only for a short time (days to one week). The main advantages to peripheral catheters are the ease of insertion, the minimal infection rate, and the low rate of other complications.

Because of the importance of maintaining central access for the long term (months, years, even decades), the care of central lines is crucial. The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has published comprehensive guidelines on the management of central venous access [20].

Lock therapy — Regardless of the type of catheter, catheter-related bloodstream infections are a major complication of PN use. Many centers are employing daily ethanol lock therapy in an attempt to decrease bloodstream infections. Typically, enough 70% ethanol to completely fill the catheter is instilled during a time when the catheter is not being used for PN. The ethanol is allowed to remain in the catheter for four hours and then removed. The catheter is then flushed with PN solution. In some circumstances (eg, PN associated liver disease and intestinal failure), there is weak evidence that ethanol lock therapy reduces blood stream infections. However, ethanol lock therapy also is associated with greater risk of thrombus and shortens the life of the catheter [21-23]. At this time there is not enough evidence to recommend its use in all situations. (See "Intestinal failure-associated liver disease in infants", section on 'Measures to prevent sepsis'.)

Taurolidine, an antibiotic, or taurolidine-citrate, have been used in place of ethanol to prevent catheter-related bloodstream infections [24-26]. (See "Routine care and maintenance of intravenous devices", section on 'Flushing and locking' and "Lock therapy for treatment and prevention of intravascular non-hemodialysis catheter-related infection".)

NUTRITIONAL ASSESSMENT — The need for PN is determined by a careful assessment of the child's nutritional status and underlying disease. Hospitalized children are at high risk for malnutrition. The nutritional assessment must be repeated at intervals as the clinical situation changes. A complete nutritional assessment includes a dietary history, anthropometrics, metabolic status, and an estimate of the nutritional requirements for the individual patient. (See "Indications for nutritional assessment in childhood".)

Dietary history — The techniques for obtaining a dietary history are discussed in a separate topic review (see "Dietary history and recommended dietary intake in children"). Patients who require PN usually have a very limited diet, or have experienced a catastrophic event that precludes or limits use of the gastrointestinal (GI) route. As a result, the dietary history is abbreviated and generally limited to medical foods (eg, formula feeds).

Anthropometrics — The most important components of a nutritional assessment are accurate measurements of weight and length or height. For infants 0 to 24 months, these are used to calculate weight for length, and for children 24 months and older, they are used to calculate body mass index (BMI). These data are plotted on the appropriate growth curves to determine percentiles and to compare with previous measurements, when available. These data can also be used to calculate Z-scores, which are valuable because they eliminate age as a variable and allow comparisons at the extremes of ranges.

Using weight-for-height Z-scores in children younger than two years or BMI-for-age Z-scores in older children, malnutrition can be categorized as follows [27,28]:

●Mild malnutrition – Z-score -1 to -1.9

●Moderate malnutrition – Z-score -2 to -2.9

●Severe malnutrition – Z-score ≤-3

The recommended growth curves and calculators for BMI and Z-scores are presented in a separate topic review. (See "Measurement of growth in children", section on 'Recommended growth charts with calculators'.)

BMI is a good index of adiposity in most patients. In patients with edema or with unusual ratios of lean tissue to fat, measurements of mid upper arm circumference and skinfold thickness can be used to assess body composition. These measurements are inexpensive and easily performed but have limited precision. (See "Measurement of body composition in children".)

Children with obesity can have macro- and micronutrient deficiencies that are masked by their over-nourished appearance. They are at risk for hepatobiliary disease, respiratory distress, renal impairment, hyperglycemia, hyperinsulinemia, and infection. These risks should be considered in the nutritional planning. (See "Overview of enteral nutrition in infants and children", section on 'Adjustments for children with obesity'.)

HOW TO PRESCRIBE PARENTERAL NUTRITION — Typically, PN for pediatric patients is tailored to the needs of the patient. This requires a series of calculations and an individualized PN prescription. A step-by-step guide to prescribing PN can be found here (table 2). This is followed by an example of PN calculations (figure 1). Target ranges for macronutrients when initiating and advancing PN are found in another table (table 3). Following these is an example of a PN order form (form 1). This order form can be converted to an order set for electronic medical records.

Standard versus individualized parenteral nutrition — Many hospitals and institutions have standard PN formulas available. Standard PN preparations have the advantages of lower cost and longer shelf life (up to 28 days), both of which are important considerations. These formulas will often meet the needs of some pediatric patients, and in these cases, standard PN preparations can be used with appropriate monitoring [29]. They can also be used as starter formulas for PN until an individualized prescription can be prepared. However, use of standard formulas becomes problematic for long-term use, when monitoring may be infrequent. Standard formulas should not replace the individualized approach, which is described below.

Initiation and monitoring — Prior to initiating PN, goals for fluids, energy, protein, carbohydrate, fat, electrolyte, mineral, and trace elements are set based on the patient's individual needs. It is important to determine whether PN is to be used for maintenance, normal growth, or nutritional repletion and catch-up growth. Anthropometric and laboratory measures must be obtained at baseline and repeated periodically after PN treatment is begun to monitor the patient and adjust the PN prescription as needed (table 4).

Although the fluid and electrolyte content of PN can be customized to the individual patient, PN should not be used as the sole fluid source in metabolically unstable patients, nor should it be used to correct electrolyte abnormalities. Instead, any significant fluid and electrolyte disturbance should be corrected with separate intravenous fluids administered via separate venous access. If hypophosphatemia is present, it should be corrected before PN is initiated because the dextrose in the PN solution will cause an intracellular shift of phosphorus that will further decrease the serum phosphorus level. Similarly, children with malnutrition typically require phosphorus and calcium repletion in quantities that cannot be accommodated in a single PN solution, so additional venous access usually is required. (See "Poor weight gain in children younger than two years in resource-abundant settings: Management", section on 'Prevention of nutritional recovery syndrome'.)

Requirements — Recommended requirements for each nutrient, along with scientific justification, can be found in the National Academy of Medicine's Dietary Reference Intakes (DRIs) and are summarized in UpToDate topic reviews. Nutrients are absorbed from the gastrointestinal (GI) tract in varying degrees, and the degree of absorption is affected by a number of factors such as simultaneously ingested foods, motility of the GI tract, and function of the digestive process. Thus, parenteral requirements are different and usually less than enteral requirements.

Fluids — Parenteral fluid guidelines are based on estimates of needs to maintain normal hydration ("maintenance" needs), and adjusted for increased or decreased losses as necessary. The Holliday-Segar method is most commonly used to calculate maintenance needs (table 5) (calculator 1) [30]. (See "Maintenance intravenous fluid therapy in children", section on 'Components of maintenance fluid therapy'.)

Many factors affect individual fluid requirements such as age, disease state, hydration status, insensible water losses, and changes in metabolic rate and respiratory rate. Infants and children generally require at least 115 mL of fluid per 100 kcal of energy provided [31]. Conditions that may alter fluid requirements are outlined in the table (table 6).

In many cases, PN is given in a volume of fluid that is considerably higher than the maintenance fluid requirements in order to meet the child's nutritional needs. Most patients can tolerate fluid administration at 30 to 50 percent above maintenance needs [31].

Appropriate fluid management also requires ongoing monitoring and adjustment according to the patient's fluid losses and level of hydration. Fluid losses should be measured frequently and replaced, and the patient's weight should be measured daily to assess the level of hydration. Specific issues that affect fluid needs include:

●GI losses through a stoma, fistula, or from short bowel syndrome, which can reach 1 to 3 liters daily. For most patients, this fluid should be measured and replaced separately from the PN prescription, unless the fluid loss is small and consistent.

●Renal maturity will affect the extent of urinary fluid losses. At birth, urinary concentrating ability is approximately 600 mOsm/kg of water, and increases to approximately 1000 to 1200 mOsm/kg by one year of age. Periods of growth decrease the renal solute load, whereas the renal solute load is higher during times of stress and catabolism [31]. Thus, urinary fluid losses are relatively high during infancy and times of stress and catabolism, and lower during times of rapid growth.

●Insensible fluid losses are higher in infants as compared with older patients, and the maintenance fluid calculation compensates for these differences. Certain conditions can increase insensible losses. For example, fever increases insensible losses by 5 mL/kg/day for each degree of temperature >38 degrees Centigrade [31]. Other conditions that increase insensible loss are extensive burns, high respiratory rate, high ambient temperature, and low humidity.

Fluid restriction may be necessary for patients who have cardiac disease, bronchopulmonary dysplasia, head trauma, and renal failure. In such patients, PN composition can be concentrated to optimize the provision of nutrients.

Energy — Accurate determination of a patient's energy needs for the PN prescription is challenging. Energy requirements vary with age, weight, and numerous other individual patient factors including fever, activity level, underlying disease, and ambient temperature.

A practical approach to determining energy needs for the PN prescription is to estimate the approximate range of energy needs, based on the patient's age and weight. Guidelines from the American Society for Parenteral and Enteral Nutrition outline the following age- and weight-based energy requirements [32].

●Term infants <6 months – 85 to 105 kcal/kg/day

●≥6 to 12 months – 80 to 100 kcal/kg/day

●≥1 to 7 years – 75 to 90 kcal/kg/day

●≥7 to 12 years – 50 to 75 kcal/kg/day

●≥12 to 18 years – 30 to 50 kcal/kg/day

After determining the approximate range for the patient's energy needs, the specific target is selected from this range based on the individual patient's characteristics, such as need for catch-up growth, factors that may alter energy requirements, and the patient's tolerance of fluid. Factors that may alter energy requirements are listed in the table (table 7). A number of alternative methods can be used to estimate energy needs such as the Harris-Benedict Equation [33] or the Schofield Equation [34]. These methods are estimates more appropriate for adults. For children and adolescents, they must be adjusted based on the weight and clinical status.

These approaches to estimating energy requirements are clinically practical, but have only fair accuracy. As an example, a study that used indirect calorimetry to measure resting energy expenditure found that the calculated estimates of energy requirements using these and other frequently employed formulas are inaccurate and lead to the prescription of overnutrition [35]. However, in most clinical settings, indirect calorimetry is not available for routine use. Therefore, it is important to monitor the patient's growth response to the PN with serial weights and adjust the energy input as needed.

Protein — Targets for protein intake for pediatric patients with normal organ function for age are as follows [32]:

●Infants (1 to 12 months) – 2 to 3 g/kg/day

●Children (>10 kg, or age 1 to 10 years) – 1 to 2 g/kg/day

●Adolescents (11 to 17 years) – 0.8 to 1.5 g/kg/day

Protein needs also depend on severity of illness. Stress factors such as sepsis, thermal injury, surgery, trauma, and stomal losses increase protein requirements. Urinary excretion of nitrogen related to steroids, diuretics, or primary renal disease also can increase the protein requirement. Protein may need to be reduced in conditions such as renal disease, hepatic failure, and inborn errors of metabolism [36].

Once the protein target is determined, the caloric content of the amino acid solution is calculated as a component of the total energy input (figure 1). PN solutions formulated with crystalline amino acids provide 4 kcal/g and are assumed to be approximately 16 percent nitrogen. Available concentrations of stock solutions range from 3 percent to 15 percent, with 10 percent most frequently used.

Amino acids are categorized according to whether or not they can be synthesized by the human body. Essential amino acids are those that cannot be synthesized by the human body; nonessential amino acids are those that can be synthesized; and conditionally essential amino acids are those that can be synthesized but, under certain conditions, are synthesized in insufficient amounts. Both essential and nonessential amino acids are provided in standard solutions. Cysteine is an amino acid that is conditionally essential for premature and term neonates. It is not thought to be needed beyond the neonatal period but may be beneficial in some instances. Cysteine is not included in crystalline amino acid solutions, because it is unstable. It can be added separately at the time of PN infusion, in the form of L-cystine hydrochloride, which is converted to cysteine [31]. The use of cysteine and glutamate in PN for neonates is discussed separately. (See "Parenteral nutrition in premature infants", section on 'Amino acids'.)

Special "pediatric" amino acid solutions contain a higher concentration of essential amino acids and lower quantities of nonessential amino acids, so that the infants' plasma amino acid patterns mimic those of healthy, breastfed neonates [37]. Whether these solutions are beneficial to older infants and children is not known, but there is some evidence that they are associated with a decreased risk of cholestatic liver disease [36]. (See "Intestinal failure-associated liver disease in infants", section on 'Pathogenesis'.)

Energy and protein are closely related. Within limits, the more energy supplied, the less protein required to achieve nitrogen balance. One systematic review found that protein intake of at least 2.8 g/kg/day and energy intake of at least 60 kcal/kg/day results in positive protein balance in critically ill, mechanically ventilated children who were parenterally fed [38].

Fat

●Dose and administration – Between 20 and 50 percent of energy needs in PN are provided as fat, in the form of an intravenous lipid emulsion (ILE). For most patients, ILE is initially prescribed to provide fat at 0.5 to 1 g/kg/day. If tolerated, the fat dose can be advanced to 3 g/kg/day (or 2 g/kg/day for older children) if needed to provide adequate energy intake (table 3).

A rare syndrome of clinical decompensation (including acute respiratory distress, metabolic acidosis, and death) has been associated with rapid ILE infusions, especially in infants [39-41]. This risk is minimized by gradual advancement to target rates and intermittent monitoring of triglycerides. Care should be taken to avoid more rapid infusions, even for a few hours. Each ILE infusion should be started slowly, and the maximum infusion rate depends on the child's age and ILE type, as outlined in the manufacturer's prescribing information [42-44]. Excessive doses of ILE may cause hypertriglyceridemia, especially in malnourished patients, as they have a reduced ability to clear triglycerides. Triglyceride levels as high as 100 to 150 mg/dL are well tolerated. However, the dose of ILE should be reduced if the triglyceride levels are consistently in excess of 150 mg/dL.

●Nutritional content – The total calories supplied by fat are calculated using the factor 10 kcals/gram of lipid and, thus, 1.1 kcal/mL for a 10 percent ILE or 2 kcal/mL for a 20 percent ILE. Because of this high concentration of energy, ILE increases the caloric density of the PN solution. ILE are sources of essential fatty acids (EFAs; primarily linoleic and linolenic acids), which must comprise at least 4 percent of total calories to prevent EFA deficiency. (See "Micronutrient deficiencies associated with protein-energy malnutrition in children", section on 'Essential fatty acid deficiency'.)

Carnitine is not present in PN solutions, yet it is necessary for transport and metabolism of long-chain fatty acids. Therefore, carnitine supplements should be added to PN for patients on PN longer than two months, at a dose of 2 to 5 mg/kg/day.

●Formulations – Soybean oil-based lipid emulsions (eg, Intralipid) are the most common form of ILE used in the United States and most other countries. They are rich in omega-6 fatty acids, which have the advantage of supplying EFAs. However, accumulating evidence suggests that soy-based ILE also may be associated with increased inflammation and liver injury, especially in infants on total parenteral nutrition (TPN), in a pattern known as PN-associated liver disease, also known as intestinal failure-associated liver disease (IFALD). Newer emulsions, such as a fish oil-based lipid emulsion (Omegaven), contain omega-3 fatty acids, which have anti-inflammatory properties. Preliminary evidence suggests that fish oil-based ILE may be useful for treating infants with PN-associated liver disease. However, fish oil-based ILE provides minimal amounts of EFA, so patients are at risk for developing EFA deficiency and should be monitored. A mixed soybean, medium-chain triglyceride, olive, and fish oil lipid emulsion has been developed (SMOFLipid), and preliminary evidence suggests that it may delay progression of IFALD [45]. The available ILE are summarized in the table, and their use for IFALD is discussed separately (table 8). (See "Intestinal failure-associated liver disease in infants", section on 'Fish oil-based lipid emulsions' and "Intestinal failure-associated liver disease in infants", section on 'Composite lipid emulsions'.)

Other strategies to prevent or treat PN-associated liver disease include limiting the total lipid dose to 1 g/kg/day and avoidance of sepsis. (See "Intestinal failure-associated liver disease in infants", section on 'General measures'.)

Carbohydrates — Glucose is the only source of carbohydrate in PN and provides 40 to 60 percent of total calories, or 60 to 75 percent of nonprotein calories. It is provided in a monohydrous form (dextrose monohydrate), which has a caloric concentration of 3.4 kcal/g, somewhat less than the concentration of carbohydrate calories in food (4 kcal/g).

For the PN prescription, the target carbohydrate dose is determined by calculating the energy (caloric) needs that are not provided by fat or protein. The doses of protein and fat may vary depending on patient needs:

The result is then converted into grams of glucose:

After calculating the target carbohydrate dose, the glucose infusion rate (GIR) should also be calculated, to ensure that the hourly carbohydrate dose is in an appropriate range (table 9).

The acceptable GIR varies with the patient's age and clinical condition (table 3). Adequate quantities of glucose are important because at glucose infusions <2 mg/kg/min, body fat is mobilized for energy and ketosis occurs. Moreover, the brain uses glucose as the primary source of energy. The brain represents 12 percent of body weight in infants, but only 2 percent in adults. Because of this difference in relative brain size, glucose utilization by infants (6 to 8 mg/kg/min) is far more than adults (2 mg/kg/min) [31,46]. It is also important to avoid excessive glucose; an excessive GIR can cause hyperglycemia, hyperosmolarity, and osmotic diuresis. Excessive glucose can increase the risk of hepatic steatosis. A healthy child can tolerate a GIR of 12 to 14 mg/kg/min, but an ill or malnourished child may not. Thus, the glucose concentration must be carefully advanced in a malnourished patient to reduce the risk of refeeding syndrome, and serum phosphorus, potassium, calcium, and magnesium should be closely monitored. Lower GIR targets are used for ventilated patients, and patients with hyperglycemia, sepsis, and cholestasis or liver disease.

Glucose is available in stock solutions of 5 to 70 percent, as dextrose monohydrate. Concentrations greater than 12.5 percent must not be used in a peripheral vein, because the high osmolarity can damage veins. Central lines can accommodate a maximum concentration of 25 percent glucose. Glucose should be initiated in an incremental fashion while monitoring for hyperglycemia (blood glucose >200 mg/dL) and glucosuria.

Electrolytes — Electrolytes are essential and must be provided in PN. Requirements for sodium, potassium, calcium, magnesium and phosphorus are included as a separate component of the PN prescription (table 10). The chloride content of the PN solution is determined by the patient's acid-base status: patients who are acidotic should be given a chloride/acetate ratio of 1:2 or less. The maximum and minimum chloride/acetate ratios are determined by the overall composition of the PN solution. The electrolyte additives typically provide approximately 30 mL fluid per liter of PN.

Calcium and phosphorus — Calcium to phosphorus ratio in PN should be close to a 1:1 molar ratio. Ratios lower than 1:1 result in elevated serum and urine phosphorus, possibly due to inadequate calcium and hence decreased utilization of phosphorus [47]. Premature infants have high requirements for calcium and phosphorus, which must be balanced against limited solubility of these nutrients in the PN solution. (See "Parenteral nutrition in premature infants", section on 'Calcium and phosphate'.)

Trace elements and minerals — Trace elements are prepared in standard packages of four, five, or six essential elements. Individual needs vary and, at times, supplements beyond what is provided in the solution or other adjustments are necessary. Key considerations are:

●Zinc is frequently supplemented in patients who have excessive GI fluid losses via ostomy output or diarrhea. There is no good parameter to monitor for zinc status, but serum zinc levels and alkaline phosphatase are used clinically.

●Selenium is an essential nutrient so patients who require PN for two months or more must receive selenium. Selenium is not included in some standard packages of trace elements, so patients on long-term PN need a trace element preparation that includes selenium.

●For copper and manganese, decreased doses may be required for patients with cholestasis. However, in this case, serum levels should be monitored. Manganese can accumulate in patients with liver disease because it is normally excreted in bile. It is speculated that manganese accumulation can contribute to the development of PN cholestasis. Levels should be checked in patients receiving PN for greater than 30 days. If high levels are found, the amount of manganese should be decreased and levels monitored.

●Chromium is a contaminant in PN solutions. Serum and urine levels should be monitored in patients on long-term PN with renal impairment.

●Aluminum is a contaminant of PN solutions. Since crystalline amino acids have replaced protein hydrolysates, aluminum contamination has decreased. However, it remains a concern. The US Food and Drug Administration requires disclosure of aluminum content and concentration on labels of parenteral compounding supplies. Some components of PN including calcium gluconate and phosphate salts, still include significant amounts of aluminum. There is no consensus to define "safe" levels of parenteral aluminum intake. Intakes of less than 4 to 5 micrograms/kg/day were recommended by the US Food and Drug Administration in 2004 [48]. However, it is often difficult to achieve exposures under these limits using available products, particularly for preterm infants who typically have high calcium needs. (See "Intestinal failure-associated liver disease in infants", section on 'Pathogenesis'.)

●Iodine is generally not included in PN; it is not provided in most trace element solutions or added to the PN. As a result, infants and children on chronic exclusive PN may develop iodine deficiency. In one report, nearly one-half of children on chronic PN had severe iodine deficiency, and one-third developed hypothyroidism [49]. Children for whom PN is their sole source of nutrition should undergo periodic monitoring of iodine status by checking serum thyroid-stimulating hormone (TSH) every six months. If serum TSH is elevated, then iodine status can be evaluated by measurement of either 24-hour urinary iodine or spot urinary iodine (and creatinine). (See "Acquired hypothyroidism in childhood and adolescence", section on 'Iodine deficiency'.)

Iron is not added to PN solutions. Instead, it must be administered orally, intramuscularly or intravenously. Iron status should be monitored every three to four months while on PN, by measuring hemoglobin, hematocrit, and iron indices (eg, serum iron, total iron binding capacity, ferritin, and/or soluble transferrin receptor levels). Because ferritin is an acute phase reactant, it is not a reliable index of iron stores in patients with inflammation. A measure of inflammation, such as C-reactive protein, can be used to exclude inflammation and validate the results of serum ferritin. Patients on long-term PN are at risk for iron deficiency. (See "Iron deficiency in infants and children <12 years: Treatment", section on 'Intravenous iron therapy'.)

Multivitamin — Multivitamins should be routinely included in the PN prescription. Pediatric preparations are commercially available in the United States under the brand names MVI Pediatric and Infuvite Pediatric. Both preparations contain the same quantities of 13 vitamins listed in the table (table 11).

For children 3 kg body weight to 11 years of age, the recommended daily dose of the pediatric parenteral multivitamin preparation is 5 mL. For infants weighing less than 3 kg, a fraction of the 5 mL dose is given. Adult intravenous multivitamin preparations and doses are given to children and adolescents over 11 years of age. Because of recurring national shortages of intravenous vitamin preparations, neither MVI Pediatric nor Infuvite Pediatric may be available. Websites that offer alternatives are given in the section below.

PHARMACY — Preparing a PN solution for pediatric patients presents special challenges for the pharmacist because infants and children cannot tolerate high fluid volumes, and they need high concentrations of calcium and phosphorus that are not necessarily compatible. Nationwide shortages of sterile injectable ingredients used for compounding PN have confronted pharmacists and nutritionists. Between 2010 and 2012 alone, important and sustained shortages have included amino acids, intravenous lipid emulsions (ILE), electrolytes and minerals including phosphate, potassium magnesium and calcium, multivitamins for infusion (particularly pediatric preparations), trace elements, and zinc [50]. Shortages continue to be an ongoing issue.

These frequent shortages require each institution or hospital to assess their supplies and develop a strategy for their institution. Prescribing providers should consider whether a nutrient can be safely administered by the oral or enteral route for an individual patient. If a shortage necessitates rationing, patients should be monitored to detect deficiencies.

A current list of updated drug shortages can be found at the following websites, along with recommendations for PN management during times of shortage.

●American Society for Parenteral and Enteral Nutrition

●The US Food and Drug Administration's Drug Shortage Program: Current Drug Shortages – Note that this information does not track regional allocation of drugs, so there may be regional shortages even if a supply is listed as available

●American Society of Health-System Pharmacists's Current Drug Shortages

CYCLING — The term "cycling" is used when the PN solution is infused at a higher rate for less than 24 hours, followed by several hours without a PN infusion. Cycling can be initiated when a patient has been stable on PN for at least one week. Generally the time off PN is increased and the infusion rate is increased to compensate, so that the total daily volume of PN is unchanged (table 12).

Cycling PN has psychological, developmental, and physiologic benefits. For children, time off of the pump allows them freedom of movement and the ability to participate in activities such as attending school and social events. For infants and toddlers, freedom of movement is important as they develop large motor skills. In addition, continuous infusion of PN usually suppresses appetite, and cycling off of PN may allow children to experience hunger, which is helpful when transitioning to oral feeds. Cycling allows the rise and fall of hormones associated with meals. Finally, continuous infusion of glucose can be associated with high levels of insulin secretion, which may contribute to hepatic steatosis and increase hepatic lipogenesis [19]. These effects can often be lessened by cycling of PN.

Cycling requires careful planning and monitoring because sudden discontinuation of a high glucose infusion can cause hypoglycemia, especially in children younger than three years of age [51]. Blood glucose levels should be closely monitored when implementing a cycling regimen. To prevent hypoglycemia, the rate of PN delivery should be tapered during the final one to two hours of the infusion. A standard practice is to decrease the infusion rate to one-half for an hour and then one-half again for a second hour, prior to stopping the infusion entirely. The patient's blood sugar should then be checked 30 to 60 minutes after PN cessation to assure tolerance. Once the patient is on a stable, cycled schedule and has shown that she/he can tolerate the drop in glucose infusion, frequent monitoring of blood sugars is no longer necessary. This practice of tapering the infusion rate and monitoring blood sugar should be employed whenever initiating cycling or discontinuing PN.

HOME PARENTERAL NUTRITION — Providing PN outside of the hospital setting ("home PN") promotes a normal lifestyle and decreases complications and medical costs. Home PN allows continuation of nutrition support in a more normal environment, facilitates the child's development and permits participation in family and social activities. Home PN is associated with fewer infections when compared with PN in the hospital, if the caretakers are appropriately trained to use sterile technique when accessing the central venous line. Home PN decreases length of the hospital stay, thus reducing the cost [52].

Indications for home PN include all those for the hospitalized patient, with the additional provisos of an adequate home environment and support in the home. Home PN should be considered when the duration of PN therapy is anticipated to be prolonged and the patient is medically stable, no longer requiring hospitalization. For infants and children, it is prudent to initiate PN in the hospital. As an inpatient the child can be monitored more closely, the family/caregivers adequately trained to provide care, and the PN tailored and adjusted to the patient's specific needs prior to discharge. The suitability of the home should be evaluated including assessment of the family members and the safety of the home environment [53]. Planning should include contingencies for times when the primary caregiver is not available, when the child becomes ill, when mechanical problems occur, and for such events as power failure. Federal and state health care programs, along with private medical insurances, have strict guidelines that must be met for reimbursement for home PN [54].

Home PN solutions are frequently compounded as "three-in-one" solutions. That means carbohydrates, fats, and amino acids along with minerals, electrolytes, and vitamins are combined as one emulsion (rather than administering the fat emulsion as a separate component, as is typically done in hospitals). Having everything in one solution allows easy administration, but adds complexity to the job of the pharmacy to ensure a stable emulsion.

Home PN should be managed with a multidisciplinary approach including clinicians, home nurses, pharmacists, dietitians, and social workers. A reliable home care company needs to be selected that has adequate mixing, storage, and delivery systems as well as staff that are trained and experienced in the management of pediatric patients. Strict monitoring of the patient, with frequent nursing and clinic visits, combined with communication with the family are key factors to achieve successful management of home PN. Suggested follow-up and monitoring protocols are outlined in the table (table 4).

PSYCHOLOGICAL ASPECTS OF PEDIATRIC PARENTERAL NUTRITION — The effect of PN on the psychological health and well-being of the child and the family is often overlooked but is critically important. PN requires a high level of care that affects quality of life for the patient and family over and above the issues surrounding the child's underlying medical problem. Administering PN is time-consuming, expensive, and intrusive into daily routines. Patients receiving PN are often troubled by the inconvenience of high intestinal output, presence of a stoma, altered body image, and fear of complications [55]. The patient may also need to remain nil per os or have a very restricted oral diet, which can be extremely challenging for a child who may not understand the rationale behind this part of their medical treatment. Our society focuses on food and sharing meals with others, especially during social and school activities, sporting events, family holiday gatherings, religious traditions, and various day-to-day activities. For families with children receiving PN who are not able to consume food orally, these seemingly innocent and celebratory times can cause added emotional stress.

It is important for health care providers to recognize and facilitate treatment of the potential psychosocial problems that may arise with the use of PN. Some common problems identified in the literature are anxiety, parent-child conflict, sibling rivalry, peer difficulty, marital discord, loss of employment (due to time away from work required for medical appointments), financial concerns, physical and emotional fatigue, social isolation, disruption of family routines, and food refusal/aversion upon reintroduction of food [8]. Some of these difficulties are amenable to treatment through psychological counseling and support. Early referral to a qualified pediatric psychologist or counselor may be helpful for many PN patients and their family members [19].

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

SUMMARY AND RECOMMENDATIONS

●Indications – Parenteral nutrition (PN) is indicated for infants and children whose gastrointestinal (GI) tract function is inadequate to support normal growth and development if nutritional support is required for seven days or more, except in premature infants and neonates, who may require earlier intervention. If the GI tract is partially functional, the enteral route should be used even if it is only able to supply a fraction of the required nutrients. A wide variety of underlying conditions may lead to a need for PN (table 1). (See 'Indications and contraindications' above.)

●Venous access – PN almost always requires central venous access, which is defined as a catheter tip in the proximal vena cava or right atrium. This is because a PN solution must have high osmolarity in order to meet most or all of the child's nutritional needs, and solutions with high osmolarity cannot be infused through a peripheral vein. (See 'Central and peripheral venous access' above.)

●Assessment – The assessment prior to prescribing PN includes anthropometrics and determination of whether acute or chronic malnutrition is present. These measures are used to determine the child's protein and energy requirements for the PN prescription. A panel of laboratory tests is performed at baseline (table 4), and the results are used to adjust the fluid and electrolyte content of the PN prescription. (See 'Nutritional assessment' above.)

●PN prescription – PN is tailored to the needs of the patient. The prescription for PN is created from a series of stepwise calculations (table 2 and figure 1). The ranges for macronutrients when initiating and advancing PN are based on the child's age (table 3), then modified by individual clinical considerations including the underlying disease state. (See 'How to prescribe parenteral nutrition' above.)

•Fluid supplied in PN is based on estimates of needs to maintain normal hydration ("maintenance" needs) and adjusted for increased or decreased losses or underlying conditions that affect fluid requirements (table 6). In many cases, PN is given in a volume of fluid that is 30 to 50 percent higher than the maintenance fluid requirements in order to meet the child's nutritional needs. Any large fluid losses through the GI tract (eg, in children with short bowel syndrome) should be measured and replaced separately from the PN. (See 'Fluids' above.)

•Energy needs are estimated based on the patient's age and weight, then modified by individual patient's characteristics, such as need for catch-up growth, the patient's tolerance of fluid, and factors that may alter energy requirements (table 7). (See 'Energy' above.)

•Protein needs are also based primarily on the patient's age and weight. These estimates are used to calculate the total protein dose per day and the energy supplied by that protein (using the factor 4 kcal/g protein). (See 'Protein' above.)

•Fat is supplied by an intravenous lipid emulsion (ILE) and provides between 20 and 50 percent of energy needs for PN. For most patients, ILE is initially prescribed to provide fat at 1 g/kg/day. If tolerated, the fat dose can be advanced to 3 g/kg/day (or 2 g/kg/day for older children). Excessive doses of fat may cause hypertriglyceridemia and also may contribute to PN-associated liver disease, especially in young infants. (See 'Fat' above.)

•Carbohydrates in PN are supplied by glucose (in the form of dextrose monohydrate) and provide 40 to 60 percent of total calories. The energy to be supplied by glucose is determined by subtracting the energy supplied by protein and fats from the patient's estimated total energy needs. The dose of glucose is then determined in grams (using the factor 3.4 kcal/g dextrose) and the glucose infusion rate (GIR; in mg/kg/minute) is calculated. The acceptable GIR varies with the patient's age and clinical condition (table 3). (See 'Carbohydrates' above.)

•Supplements of electrolytes and minerals (table 10), trace elements, and multivitamins are required in PN and are included as a separate component in the prescription. (See 'Electrolytes' above and 'Trace elements and minerals' above and 'Multivitamin' above.)

Patients should be monitored for nutrient deficiencies (table 4); iodine deficiency is common in patients on long-term PN and may result in hypothyroidism. The electrolyte doses can be adjusted to some degree according to the patient's needs, but PN should not be used to correct significant electrolyte abnormalities.

●Cycling PN – Cycling PN (infusing the PN solution for less than 24 hours daily) has psychological, developmental, and physiological benefits and should be implemented when possible, with care to avoid hypoglycemia. (See 'Cycling' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jessica Briggs, RD, who contributed to earlier versions of this topic review.