Todd W. Mattox and Catherine M. Crill
Four steps to developing a successful nutrition plan include definition of nutrition goals, determination of nutrition requirements, determination of appropriate route of delivery of nutrients, and subsequent monitoring of the nutrition regimen to evaluate suitability of the regimen as a patient’s clinical condition changes and to minimize or treat complications.
The appropriate route of nutrition support depends on the functional condition of the patient’s gastrointestinal (GI) tract, risk of aspiration, expected duration of nutrition therapy, and clinical condition.
Identifying the patient who is most likely to benefit from parenteral nutrition (PN) therapy includes consideration of the patient’s age, nutrition status, expected duration of GI dysfunction, and potential risks of initiating therapy.
PN formulations include IV sources of protein, dextrose, fat, water, electrolytes, vitamins, trace elements, and other additives.
PN solutions may be appropriately formulated for administration by peripheral or central venous access.
PN solutions may be infused continuously or intermittently.
Biochemical and clinical measurements considered necessary for effective monitoring of patients receiving PN include serum chemistries, vital signs, weight, total daily fluid intake and losses, and nutritional intake.
Non–catheter-related complications of PN therapy are minimized with application of age-appropriate nutrient dosing guidelines, frequent monitoring, and rational adjustments to the PN regimen when metabolic abnormalities occur.
Individualized PN therapy is based on goals determined from a patient-specific nutrition assessment, type of available IV access, and macronutrient and micronutrient requirements. Nutrient requirements are affected by age, degree of metabolic demand, organ function, other drug therapy, exogenous losses, acid–base status, and enteral intake in patients with recovering GI function.
Maintenance of adequate nutrition status during illness has been recognized for more than 50 years as an integral part of the medical treatment plan for patients who are unable to use normal physiologic means of nourishment. Successful techniques for providing IV nutrition support were introduced to clinical practice in adults and subsequently, infants in the late 1960s.1 Use of central venous access was investigated to reduce risk of metabolic complications associated with fluid overload and electrolyte imbalances. The use of larger vessels permitted infusion of concentrated formulas, which decreased the fluid volume required and avoided the phlebitis that commonly occurred when hypertonic infusions were given peripherally.
Further clinical experience and research fostered development of protocols that promoted better patient care and resulted in a decline in complications associated with parenteral nutrition (PN) therapy.2 The scope of practice for nutrition support clinicians has broadened as a result of increasing knowledge regarding the metabolic consequences associated with acute injury and chronic disease states. The pharmacist’s role in providing safe and effective nutrition-support care requires knowledge of the principles of patient selection, initial therapy design, preparation and dispensing of the nutritional formulations, outcome monitoring, and strategies for providing therapy during PN product shortages.3 Other responsibilities of the nutrition support pharmacist may include development of policy and procedures as well as quality improvement activities for patient care and operational processes associated with providing parenteral and enteral nutrition.4–6 However, the role of other healthcare professionals may be similar because of the evolving interprofessional approach to nutritional support.7–9 This chapter reviews indications for PN, components of PN formulations, routes of IV administration, practical aspects of regimen design, solution admixture, outcome monitoring, and management of complications for both adult and pediatric (neonates, infants, and children) patients.
The primary objective of nutrition support therapy is to promote positive clinical outcomes of an illness and improve a patient’s quality of life. Four fundamental steps are key to providing optimal care for patients who require nutrition support. They are definition of nutrition goals, determination of nutrient requirements for achievement of the nutrition goals, delivery of the required nutrients, and subsequent assessment of the nutrition regimen.5,6
A patient’s nutrition goals can be established after a thorough nutritional assessment (see Chap. 118). Nutrient requirements and an appropriate route for delivery of the required nutrients can then be determined. Nutrition support goals include correction of the patient’s caloric and nitrogen imbalances and any fluid or electrolyte abnormalities or known vitamin or trace element abnormalities. An additional goal is to lessen the metabolic response to injury by minimizing oxidant stress and favorably modulating immune response. These interventions should not cause or worsen other metabolic complications.
The gastrointestinal (GI) tract is the optimal route for providing nutrients unless obstruction or other GI complications are present (see Chap. 120).10,11 Other considerations that may impact determination of an appropriate route for delivery of nutrition support include expected duration of nutrition therapy and risk of aspiration. Patients who have nonfunctional GI tracts or are otherwise not candidates for enteral nutrition may benefit from PN.
INDICATIONS FOR PARENTERAL NUTRITION SUPPORT
The association between malnutrition and development of complications and mortality is well documented for adult and pediatric patients.11,12 Although improvement in nutrition status as defined by various clinical nutrition markers has been reported for patients who received PN, the impact on clinical outcome is difficult to demonstrate in many adult populations. Several investigations have reported a positive effect of PN on complications and mortality, but others have failed to demonstrate any difference.10,13 Early studies have been criticized for defects in study design, such as small sample sizes, inappropriate randomization, and inconsistent baseline nutrition status among the study group, which hindered demonstration of the effectiveness of PN therapy. The impact of PN on clinical outcome has been more successfully demonstrated for critically ill infants and children, particularly those with acquired or congenital GI tract anomalies.14 Consensus guidelines for PN use for adults (Table 119-1) and pediatric (Table 119-2) patients are based on clinical experience and investigations in specific patient populations.10,11,13–18Unfortunately, conflicting data have resulted in a lack of consistency in published guidelines from different sources, which complicates identification of the patient who is most likely to benefit from PN. However, these published reports may serve as resources for development of institution-specific standards.
TABLE 119-1 Indications for Adult Parenteral Nutrition
TABLE 119-2 Indications for Pediatric Parenteral Nutrition
The decision to initiate PN is based on the assessment that the patient cannot meet his or her nutritional requirements through the GI tract. This assessment must include an evaluation of the patient’s nutrition status, clinical status, age, and potential risks of initiating therapy (e.g., infection and other metabolic abnormalities). The appropriate length of time to wait before starting PN therapy depends on patient age and clinical status.10,11,13–18 Adult PN therapy is not an emergent intervention and should not be initiated until the patient is hemodynamically stable.10 In general, previously well-nourished, clinically stable adults who are not candidates for enteral nutrition should be considered candidates for PN after 7 to 14 days of suboptimal nutritional intake.10,13 Guidelines for use in infants and children are primarily influenced by age. The most appropriate time to initiate therapy for infants and children varies with age and nutritional status. Early PN within the first 24 hours of life has been recommended for extremely low-birth-weight infants whose protein loss can be twofold higher than in term infants and frequently results in a negative nitrogen balance that cannot be corrected by glucose as a sole nutrient.19Early aggressive PN in neonates can enhance protein accretion and somatic growth.19,20 Although there has been some concern regarding protein tolerance with early initiation of PN, most clinicians now support the practice. Withholding PN for 2 to 3 days after birth, coupled with a slow advancement of substrate, only appears to contribute to the acute semistarvation and growth failure seen for many neonates.19,20 PN should be initiated within 5 to 7 days for other pediatric patients who are unable to meet their nutrient requirements with enteral nutrition.14 Earlier intervention should be considered for term infants (within 2–3 days), critically ill children (within 3–5 days), and children with preexisting malnutrition. Guidelines for older children are similar to those for adults.
Some guidelines advocate for early PN use to correct the resulting protein-energy deficit that has been associated with worse clinical outcome in some studies, but others recommend withholding PN support in previously healthy patients until at least 7 days after admission to the intensive care unit.
COMPONENTS OF PARENTERAL NUTRITION
Parenteral nutrition formulations include IV sources of protein, dextrose, fat, water, electrolytes, vitamins, trace elements, and other additives. PN solutions should provide the optimal combination of macro- and micronutrients to provide a patient’s specific nutritional requirements. Macronutrients include water, protein, dextrose, and IV fat emulsion (IVFE) (Table 119-3). Micronutrients include vitamins, trace elements, and electrolytes. Both macronutrients and micronutrients are necessary for maintenance of normal metabolism. In general, macronutrients are used for energy (dextrose and fat) and as structural substrates (protein and fat). Micronutrients are required to support a variety of metabolic activities necessary for cellular homeostasis such as enzymatic reactions, fluid balance, and regulation of electrophysiologic processes.
TABLE 119-3 Macronutrient Components of Parenteral Nutrition Solutions
Parenteral nutrition component availability has been adversely affected by intermittent product shortages. Over the past several years, shortages of all PN components except concentrated dextrose have been reported.3 The unavailability of these products has resulted in delays in PN therapy, restricted or precluded nutrient dosing, and had negative effects on all steps of the PN process that have compromised patient safety. Strategies for providing safe therapy during PN product shortages can be challenging for PN patients and practitioners. Conservation recommendations and alternative therapy measures are available.3
Protein in PN solutions is provided in the form of crystalline amino acids (CAAs), which are used primarily for protein synthesis. When oxidized for energy, 1 g of protein yields 4 cal (or ∼17 J). However, including the caloric contribution from protein when calculating calories provided by the PN regimen is controversial.21
Commercially available CAA solutions may be categorized as standard amino acid solutions or modified amino acid solutions. Standard CAA solutions are designed for patients with “normal” organ function and nutritional requirements (see Table 119-3). Although standard CAA solutions differ in the proportion of specific amino acids, they contain a balanced profile of essential, semi-essential, and nonessential L-amino acids. Despite these differences, similar effects on markers of protein use have been reported.22 The protein concentration, total nitrogen, and electrolyte content are also different among products. Because the nitrogen concentration of dietary protein is approximately 16%, 6.25 (100 g protein/16 g nitrogen) is commonly accepted as the conversion figure for calculating the nitrogen amount provided by CAA protein. Differences in nitrogen content per gram of amino acids among CAA products may affect calculation of nitrogen amounts infused when determining nitrogen balance.22,23 The clinical significance of these differences in determining nitrogen balance for routine clinical use is unknown.23
Electrolyte composition of standard CAA solutions varies from small, obligatory amounts to the provision of maintenance requirements of most electrolytes for an adult. Electrolytes provided by CAA solutions must be considered when determining a patient’s individual requirements. CAAs are available in several different concentrations, which facilitates compounding of patient-specific PN regimens. Use of highly concentrated products (15%–20%) is attractive for critically ill patients who typically require fluid restriction but have large protein needs. Modified amino acid solutions are designed for patients who have altered protein requirements, such as those with hepatic encephalopathy, renal failure, and metabolic stress or trauma, as well as for neonates and pediatric patients (see Table 119-3). These solutions tend to be more expensive than standard CAA solutions. The rationale for and clinical efficacy of modified amino acids in disease-specific PN regimens is controversial.10,17,24–27
Several commercially available CAA solutions are designed to provide conditionally essential amino acids, which are considered nonessential during health because they are produced from other amino acids. However, under certain physiologic conditions, such as prematurity or sepsis, these amino acids cannot be synthesized in sufficient quantities.22 CAA solutions specifically designed for neonates and pediatric patients contain increased amounts of taurine, aspartic acid, and glutamic acid. Other conditionally essential amino acids, such as cysteine, carnitine, and glutamine, are not available in commercial CAA solutions in pharmacologic amounts because they are relatively unstable or poorly soluble.22
Exclusive use of standardized, commercially prepared premixed IV products has been advocated for use to improve medication safety. However, American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) has reported that patient safety data do not support the general use of standardized PN formulations across healthcare organizations.
Consequently, PN solutions may need to be modified to provide the desired amount of supplemental conditionally essential amino acids. For example, cysteine is a conditionally essential amino acid for preterm and term infants because of their enzymatic immaturity of the trans-sulfuration pathway. Cysteine may be added to PN solutions at the time of compounding as a supplement to CAA solutions and to enhance calcium and phosphate solubility by decreasing solution pH.24 Carnitine is a quaternary amine required for long-chain fatty acid transport into the mitochondria for β-oxidation and energy production. Newborns are at risk for carnitine deficiency because of their immature biosynthetic capacity. Decreased plasma carnitine concentrations have been reported for infants and children receiving PN without carnitine.28 Supplemental carnitine may be added to the PN solution at the time of compounding. Although the benefit of carnitine supplementation in PN has not been clearly identified, positive effects on nutritional markers, including improved fatty acid oxidation, weight gain, and nitrogen balance, have been documented. In general, carnitine supplementation is reserved for neonates expected to receive PN support for 7 days or longer.28
Glutamine is the most abundant free amino acid in the body and is an important intermediate for many metabolic processes. Glutamine is reported to have an important role in maintaining intestinal integrity, immune function, and protein synthesis during conditions of metabolic stress.29 Investigations in humans and animals have reported positive effects on nutritional markers such as nitrogen balance, but others have reported significant improvement in other outcome markers, such as decreased length of hospitalization, incidence of infections, and GI toxicities associated with chemotherapy or radiation.29 However, the best adult candidate for response to glutamine therapy has not been clearly identified.29 The clinical usefulness of glutamine in neonates and infants is less clear.29–31 Plasma glutamine concentrations increase with supplementation, but no beneficial effect on sepsis, enteral feeding tolerance, necrotizing enterocolitis, growth, or mortality has been reported.29–31 The clinical use of glutamine is further complicated because there is no parenteral glutamine formulation commercially available in the United States. Currently available CAA solutions do not contain glutamine because of poor solubility and instability. Use of parenteral glutamine requires special manufacturing techniques not readily available in many institutional pharmacies.29 However, parenteral glutamine is available from several licensed pharmacies that extemporaneously compound L-glutamine crystalline powder under sterile conditions either as a separate parenteral solution or as a part of a CAA solution.
The primary energy source in PN solutions is carbohydrate, usually in the form of dextrose monohydrate, which is available in concentrations ranging from 5% to 70%. When oxidized, each gram of hydrated dextrose provides 3.4 kcal (14.2 kJ). The appropriate IV dextrose dose depends on the patient’s age, estimated caloric requirements, and clinical condition. For example, minimum dextrose requirements for neonates are estimated to be approximately 6 to 10 mg/kg/min.16,20 However, IV dextrose infusion rates should not exceed 14 to 18 mg/kg/min for infants or 4 to 7 mg/kg per minute for adults.16,32 The recommended dextrose dose for routine clinical care rarely exceeds 5 mg/kg per minute for older critically ill children (1–11 years old) and adults.16,32 Maintaining an age-appropriate dextrose infusion rate is necessary to minimize risk of adverse effects. If the dextrose infusion rate exceeds the glucose oxidation rate, metabolically expensive pathways, such as glycogen repletion and lipid synthesis, are favored, resulting in increased energy expenditure, increased oxygen consumption, and increased carbon dioxide production. Excessive dextrose infusion rates also may contribute to the development of hyperglycemia and an increase in the concentration biochemical markers for liver function associated with fatty infiltration of the liver.32,33
Carbohydrate sources that are not insulin dependent have been investigated as an alternative to dextrose to improve glycemic control for patients with impaired insulin secretion or activity who require PN. Glycerol, a sugar alcohol that provides 4.3 kcal/g (18 kJ/g), is the only dextrose alternative commercially available. It is available as an isotonic, 3% solution in combination with 3% amino acids and supplemental electrolytes (ProcalAmine, B. Braun Medical, Irvine, CA). Although the solution may be peripherally infused, a major disadvantage of this formula is the dilute amino acid and carbohydrate concentrations. Most adult patients require up to 3 to 4 L/day of ProcalAmine solution together with IVFE as a caloric source to provide minimum energy requirements.34 IV glycerol use for catabolic adults is safe and effective, but similar data are not available for infants and children.35
IV Fat Emulsion
IVFE is used as a concentrated source of calories and essential fatty acids. Although commercially available IVFE products have traditionally contained soybean oil or a combination of soybean oil and safflower oil, IVFE products containing safflower oil are no longer manufactured. Soybean oil–based IVFE products are available in various concentrations (10%, 20%, and 30%) and contain egg phospholipids as an emulsifying agent and glycerol to make the emulsion isotonic. Although the caloric contribution of fat is 9 kcal/g (38 kJ/g), the caloric content of IVFE is 1.1 kcal/mL (4.6 kJ/mL) for 10% emulsion, 2 kcal/mL (8.4 kJ/mL) for 20% emulsion, and 3 kcal/mL (12.6 kJ/mL) for 30% emulsion because of the caloric contribution of the egg phospholipid and glycerol.16 The fatty acid composition of soybean oil–based IVFEs is approximately 44% to 62% linoleic acid and 4% to 11% linolenic acid.36 Linolenic acid, an omega-3 fatty acid, and linoleic acid, an omega-6 fatty acid, are both polyunsaturated long-chain triglycerides (LCTs).36 IVFE products differ in phospholipid and triglyceride concentrations. Higher concentrated IVFEs (20% and 30%) have a lower phospholipid-to-triglyceride ratio compared with 10% IVFE.16,37 Because higher amounts of circulating phospholipids are associated with impaired triglyceride clearance in neonates and infants, 20% IVFE is the preferred product for this population.16,37
Soybean oil–based IVFE is effective for treatment or prevention of essential fatty acid deficiency (EFAD). EFAD is the result of a biochemical deficiency of linoleic acid and arachidonic acid, which are considered essential for humans.38 Linoleic and linolenic acids are important for a variety of functions such as cellular integrity, platelet function, postnatal brain development, and wound healing.38 Normally, linoleic acid is converted to the tetraenearachidonic acid. When linoleic acid is not present in sufficient amounts, oleic acid is converted to the triene 5,8,11-eicosatrienoic acid, a fatty acid of lesser physiologic integrity, and EFAD occurs. EFAD may be prevented by providing 2% to 4% of total calories as linoleic acid and 0.25% to 0.5% of total calories as linolenic acid.39 This may be achieved for most adult patients by giving approximately 100 g IVFE weekly.32,39 Neonates and infants require a minimum of 0.5 to 1 g/kg daily.16,37
Plasma IVFE clearance is directly related to gestational age of infants and appears to be influenced by the infusion rate and the patient’s clinical status.37,40 The risk of developing hypertriglyceridemia decreases with longer infusion times.37,39,40 Rapid IVFE infusions are reported to contribute to decreased oxygenation for neonates.40,41 Adverse pulmonary effects are thought to be caused by polyunsaturated fatty acid (PUFA)–driven prostaglandin production, which results in altered vascular tone. Although the association between IVFE and pulmonary dysfunction is not clear, a black box warning appears in the Food and Drug Administration (FDA) labeling for soybean oil–based IVFE that acknowledges deaths in preterm infants associated with pulmonary fat accumulation thought to be related to IVFE infusions.40,42 In addition, data for animals and humans also suggest that rapid infusion of long-chain fatty acid formulations may have a negative impact on immunocompetence by saturating the reticuloendothelial system.32,43
As a caloric source, IVFE use may facilitate provision of adequate calories and minimize complications of nutrition therapy such as hyperglycemia, hepatotoxicity, or increased carbon dioxide production.32Although the frequency of acute adverse effects is reported to be less than 1% with current formulations, patients receiving their first IVFE dose should be monitored for dyspnea, chest tightness, palpitations, and chills. Headache, nausea, and fever also have been reported and might be associated with a rapid infusion rate. In general, IVFE use is contraindicated for patients with an impaired ability to clear fat emulsion, such as patients with pathologic hyperlipidemia, lipoid nephrosis, and hypertriglyceridemia associated with pancreatitis.42 Finally patients with a reported egg allergy should be evaluated carefully for the nature and severity of the reaction before deciding to initiate a fat-based PN regimen.
Commercially available 10% and 20% IVFE products may be administered by either the central or the peripheral route. They may be added directly to the PN solution as a total nutrient admixture (TNA), also referred to as a three-in-one system (lipids, protein, glucose, and additives), or they may be piggybacked with the CAA-dextrose solution, commonly referred to as a two-in-one solution.39,42 The more concentrated 30% IVFE is only approved for use in the preparation of TNA and is not intended for direct IV administration.
Soybean oil–based IVFEs have negative effects on immune function as the result of omega-6 PUFA influence on proinflammatory eicosanoid production. These negative effects on immune function have stimulated a search for alternative IVFE sources that provide adequate essential fatty acids but lower amounts of omega-6 FA.36,43 Medium-chain triglycerides (MCTs) may offer several advantages, especially for critically ill patients. MCTs are hydrolyzed and cleared more rapidly than LCTs, and they do not accumulate in the liver. In addition, MCTs do not require carnitine for entrance into mitochondria for oxidation. However, MCTs are not a source of essential fatty acids. Subsequent studies of IV MCT-LCT mixtures in a number of patients demonstrate safety and efficacy comparable with standard LCT emulsions.36,43 Several MCT-LCT products are available in Europe, although no IV MCT formulations are currently available commercially in the United States. Other IVFE that are available outside the United States include a fish oil-based emulsion, an olive oil–and soybean oil–based emulsion and mixed fat source emulsions, including a soybean, MCT, olive oil, and fish oil combination and a soybean, MCT, and fish oil combination.36,43 Fish oil–based IVFE contain predominantly omega-3 PUFAs, which are metabolized to cytokine mediators that may be less inflammatory and immunosuppressive than those derived from omega-6 PUFAs. Olive oil–based IVFEs provide essential fatty acids, are a rich source of vitamin E, and may have a neutral effect on immune function. The clinical effect of IVFE administration on immune function, as well as on patient morbidity and mortality, is not clear.36,43 However, investigations of enteral solutions with a higher concentration of omega-3 PUFAs have reported decreased infections and improvement of in vitro immunologic indices in critically ill patients.38,44 Recent evidence suggests that soybean-based IVFE, which contains phytosterols and predominantly omega-6 PUFAs, may play a greater role in the development of PN-associated liver disease (PNALD). Investigations of fish oil–based IVFE have reported improvement in or reversal of PNALD.36,45
The association between soybean oil–based IVFE and PNALD has stimulated modifications to standard clinical practice, including soybean oil–based IVFE restriction and the replacement of soybean oil–based IVFE with fish oil–based IVFE. When reducing or eliminating soybean oil–based IVFE from the parenteral diet, debate exists with respect to whether the decreased amount of long-chain fats provided is sufficient to prevent essential fatty acid deficiency.
Although IVFE products remain the most common source of parenteral fat, a number of drugs have been introduced that contain lipid either as a vehicle for delivery or as a portion of the drug molecular formulation. Propofol, an IV anesthetic, is delivered in a soybean-oil-in-water emulsion that has essentially the same composition and caloric concentration as 10% IVFE. This agent is used commonly for continuous sedation of ventilated patients and should be considered a potentially significant source of calories that may require adjustment of a patient’s nutrition regimen.46 The antifungal amphotericin B is available in several lipid-containing combinations such as liposomal and lipid complex formulations. The caloric contribution from these products when used in standard doses generally is small and is not relevant clinically.
Maintenance guidelines for daily parenteral vitamin supplements were initially established in 1975 by the Nutrition Advisory Group of the American Medical Association (NAG-AMA) for adults, children, and infants.47 The NAG-AMA identified 13 essential vitamins that include four fat-soluble vitamins and nine water-soluble vitamins based on requirements for healthy people. Revised recommendations to these original guidelines were made in 1985 and again in 1988 based on clinical experience and research for specific adult and pediatric patient groups who required PN.47
For example, the NAG-AMA guidelines for infants and children were later revised to primarily reflect changes for preterm infants requiring PN.47 In addition, the U.S. FDA mandated reformulation of adult parenteral multiple-vitamin product guidelines to include 150 mcg of vitamin K in addition to higher doses of vitamins B1, B6, and C compared with the original AMA-NAG recommendations.47
Vitamin K was not included in previous parenteral multiple-vitamin formulations to minimize the risk of a drug–nutrient interaction for patients receiving anticoagulants, which antagonize vitamin K–dependent coagulation factors. The NAG-AMA recommendation for vitamin K for adults is 2 to 4 mg weekly. Other practitioners recommend larger doses of 0.5 to 1 mg/day or 5 to 10 mg weekly.39 An investigation of patients receiving long-term IVFE-containing PN with vitamin K–free parenteral multivitamins at home suggests that supplemental vitamin K may not be necessary to maintain normal prothrombin times and plasma vitamin K concentrations.48 Soybean oil used in IVFEs is a natural source of phylloquinone (vitamin K1). However, the vitamin K concentration is dependent on the soybean oil concentration in the IVFE.48–50 Mean concentrations of 30.9 and 67.5 mcg/100 mL were reported for 10% and 20% Intralipid (Baxter Health-care Corporation, Deerfield, IL), a soybean oil–based IVFE. The bioavailability of vitamin K1 from IVFEs is unknown. Although hospitalized patients who received no additional vitamin K supplementation during short-term PN that included a low vitamin K–containing IVFE experienced minimal effects on international normalized ratio, supplemental vitamin K may be given intramuscularly or subcutaneously or added to the PN solution if needed.49 Current recommendations suggest supplemental vitamin K is unnecessary when a vitamin K–containing multiple-vitamin product is used.39
Adult parenteral multiple-vitamin products formulated to comply with the FDA-mandated changes to the NAG-AMA guidelines are available commercially. In addition, a parenteral multiple-vitamin formulation containing no vitamin K is commercially available for adult patients receiving home PN and warfarin anticoagulation (MVI-12, multivitamin infusion without vitamin K; Hospira, Inc. Lake Forest, IL). Two parenteral multiple-vitamin products are commercially available for use for pediatric patients. MVI-Pediatric (Hospira Inc.) and Infuvite Pediatric (Baxter Health-care Corporation) are formulated to meet the revised NAG-AMA guidelines for infants weighing less than 1 kg (<2.2 lb) to children up to 11 years old. However, there are no commercially available IV multivitamin products designed to specifically meet the unique requirements of premature infants, including higher vitamin A and lower doses of vitamins B1, B2, B6, and B12 compared with recommendations for term infants and older children.
Vitamin requirements may be altered in malnutrition and other specific disease states or with certain drug therapies. Individual and combination products are available to provide additional or tailored supplementation, which may be necessary to prevent development of vitamin toxicities or deficiencies caused by altered metabolism or drug therapy.
The 2012 A.S.P.E.N. recommendations question whether the vitamin D content of parenteral multivitamins is adequate to meet current RDAs and advocate for a parenteral vitamin D product for PN-dependent patients who are unresponsive to additional enteral vitamin D supplementation.47 In addition, the recommendations support the continued production of adult multivitamin products with and without vitamin K and for the supplementation of carnitine (2–5 mg/kg/day) in neonatal PN and choline in all patients receiving PN.47
Many trace elements are an important part of metalloenzymes and function as cofactors in a variety of regulatory metabolic pathways.51,52 Although 17 trace elements have demonstrated biologic importance, clear deficiency syndromes in humans have been described only for cobalt (as vitamin B12), copper, iodine, iron, and zinc.52–54 In 1979, the NAG-AMA recommended chromium, copper, manganese, and zinc supplementation for patients receiving PN.47,52 Recommendations followed in 1984 to also supplement with selenium.47,52 Although a clear deficiency syndrome for manganese has not been reported in humans, the NAG-AMA considered manganese essential based on case reports of patients receiving PN with metabolic complications that corrected after manganese supplementation. Reports of syndromes associated with selenium and molybdenum deficiency suggest that they also may be essential.52,53 Although iodine deficiency has not been reported for patients receiving short-term PN, it has been observed for patients receiving long-term PN and may be related to the use of chlorhexidine for central-line care instead of povidone–iodine.55
IV trace elements are available as single-trace element solutions and as multiple-trace element combinations. Most products for adults provide the daily requirements for the trace elements considered essential by the NAG-AMA (i.e., chromium, copper, manganese, selenium, and zinc). Currently available combination products for neonates and pediatric patients contain only chromium, copper, manganese, and zinc. Combination products containing iodide and molybdenum are no longer commercially available in the United States. Single-entity IV products are available that allow for individualization of trace mineral supplementation of chromium, copper, iodine, manganese, selenium, and zinc; however, recent shortages have threatened the supply of these single-entity products.
Requirements for trace elements also change depending on the clinical condition of the patient. For example, higher doses of supplemental zinc likely are necessary for patients with high-output ostomies or diarrhea because the GI tract is the predominant excretion route for zinc. Whereas manganese and copper are excreted through the biliary tract, chromium, molybdenum, and selenium are excreted renally. Hence, these trace elements should be restricted or withheld from PN solutions for patients with cholestatic liver disease and renal failure, respectively.
A.S.P.E.N. recommended formulation changes to the available multiple-trace element preparations for PN patients.47 The recommendations support overall decreased contamination of trace elements in large- and small-volume PN products.47 The recommendations advocate for decreased copper and manganese, no (or decreased) chromium, and inclusion and increased dose of selenium in all adult multiple-trace products.47 The recommendations also support products with no chromium, decreased manganese, and the inclusion of selenium in all pediatric multiple-trace products.47
Electrolytes such as sodium, potassium, calcium, magnesium, phosphorus, chloride, and acetate are necessary PN components for the maintenance of numerous cellular functions. Electrolytes may be given to maintain normal serum concentrations or to correct deficits. Patients who have “normal” organ function and relatively normal serum concentrations of any electrolyte should receive normal maintenance electrolyte doses when PN is initiated and daily thereafter. Specific electrolyte requirements vary according to the patient’s age, disease state, organ function, previous and current drug therapy, nutrition status, and extrarenal losses. Electrolytes are available commercially as single- and multiple-nutrient solutions. Multiple-electrolyte solutions are useful for stable patients with normal organ function who are receiving PN. Concentrated multiple-electrolyte solutions designed for addition to PN solutions generally contain only sodium, potassium, calcium, and magnesium. Phosphorus must be added as a separate additive. Further information regarding metabolism and requirements of vitamins, trace elements, and electrolytes is given elsewhere.39,56
DESIGNING A PARENTERAL NUTRITION REGIMEN
Several factors, including the patient’s venous access, fluid status, and macronutrient and micronutrient requirements, are important considerations when designing the PN regimen. A patient’s venous access and fluid status determines how concentrated the PN solution may be compounded and hence have an impact on the nutrient amount that may be provided. PN solutions may be administered by central or peripheral venous access. The patient’s clinical condition determines which route is most appropriate.
Parenteral nutrition solutions may be provided as a two-in-one formulation that contains dextrose, CAA, and other necessary micronutrients or as a three-in-one formulation or TNA that contains dextrose, CAA, and IVFE, as well as other necessary micronutrients. Use of TNA solutions offers several potential advantages, including reduced inventory (infusion pumps, tubing, and other related supplies), decreased time for compounding and administration, a potential decrease in manipulations of the infusion line (which should correspond with a decreased risk of catheter contamination), and ease of delivery and storage for patients receiving home PN.57 Potential disadvantages include increased risk of infections and stability and compatibility concerns. For example, the stability of TNA solutions is less predictable than that of two-in-one solutions, which makes their use less desirable in specific patient populations such as neonates and infants.39
Routes of Parenteral Nutrition Administration
Peripheral parenteral nutrition (PPN) is an option for mild to moderately stressed patients for whom central access is unavailable or undesirable and function of their GI tract is expected to return within 10 to 14 days.58 Potential PPN candidates should not be fluid restricted or require large nutrient amounts. Lower concentrations of amino acid (3%–5% final concentration), dextrose (5%–10% final concentration), and micronutrients compared with central parenteral nutrition (CPN) are necessary for peripheral administration. Because PPN solutions are relatively dilute, larger volumes are usually necessary to provide nutrient requirements. Additionally, many patients who receive PPN likely will require the use of IVFE to increase caloric support to levels more consistent with CPN regimens. The primary advantages of PPN include a lower risk of infectious, metabolic, and technical complications.58 However, several other factors may complicate PPN use in many patient populations. Patients who have received multiple courses of chemotherapy, malnourished patients, premature infants, elderly patients, and others with an illness of long duration who have already been subjected to multiple venous accesses for fluid and medication administration are likely to have limited peripheral venous access. PPN use is also limited by relatively poor peripheral vein tolerance to hypertonic solutions. Thrombophlebitis is a commonly reported complication for patients receiving PPN. Although the risk of developing phlebitis is greater with solution osmolarities greater than 600 to 900 mOsm/L (>600–900 mmol/L), peripherally administered TNA with much higher osmolarities has been associated with low infusion-site complications in some centers.58 Efforts to minimize development of phlebitis or infiltration sequelae for patients receiving PPN include addition of IVFE to the regimen as a possible venous lumen protectant, subtherapeutic heparin doses (0.5–1 unit/mL) to prevent thrombus formation, or small doses of hydrocortisone (5 mg/L) to minimize access site inflammation.58 However, heparin is not compatible for use in TNA formulations. Midline catheter use may offer some advantage and has been associated with a reduced risk of thrombophlebitis.59 Although these catheters are not central venous access devices, they are longer and infuse into larger venous vessels that may dilute the PN solution to a more tolerable osmolarity. The osmolarity of a PN solution may be estimated by using the guidelines for osmolarities of selected PN components in Table 119-4.
TABLE 119-4 Osmolarities of Selected Parenteral Nutrients
Central parenteral nutrition is the preferred choice for PN delivery and is used predominantly for patients who require PN for periods of more than 7 to 14 days during hospitalization or indefinitely at home.39,60 These patients may have large nutrient requirements; poor peripheral venous access; or fluctuating fluid requirements, such as metabolically stressed patients with extensive surgery, trauma, sepsis, multiple-organ failure, or malignancy. CPN solutions are highly concentrated hypertonic solutions that must be administered through a large central vein. Unlike peripheral veins, central veins have a higher blood flow, which quickly dilutes the hypertonic solutions. Disadvantages of CPN include risks associated with catheter insertion, routine catheter use, and care of the access site. Relative to peripheral venous access, central venous catheter (CVC) access is associated with a greater potential for infection. In addition, the risk of more serious catheter-induced trauma and related sequelae and other serious technical or mechanical problems is greater than that with peripheral access.
The choice of central venous access site depends on a number of factors, including the patient’s age and anatomy. CVCs vary in composition, lumen size, number of injection ports, and other special features that affect ease or convenience of care and maintenance. CVCs for short-term use for adults are commonly inserted percutaneously into the subclavian vein and advanced so that the tip is at the superior vena cava.59 If this approach is not possible, the internal jugular vein can be used. Frequently, short-term central venous access is obtained for critically ill neonates via a catheter placed in the umbilical vein. Other sites for central venous access in infants and older children are similar to those in adults. When therapy is expected to last longer than 4 weeks, the catheter usually is tunneled subcutaneously before entering the central vessel, secured initially with retaining sutures, and anchored in place with a felt cuff that promotes subcutaneous fibrotic tissue growth around the catheter. The injection port may remain external or may be concealed entirely beneath the skin. Implanted CVCs have a larger port or reservoir that is surgically placed beneath the skin surface and anchored in the chest wall muscle. Peripherally inserted central catheters (PICCs) are venous access devices that are inserted into a peripheral vein (basilic, cephalic, or brachial) and advanced so that the tip is at the superior vena cava.59 PICCs are increasingly used for both short- and long-term central venous access in acute or home care settings because of ease and economy of bedside placement.39,60
Constructing a Parenteral Nutrition Regimen
After the route of delivery is chosen, components of the PN regimen are determined based on the patient’s nutritional assessment. Some healthcare systems may require the entire PN formula to be written in individual components and additives without the use of a standard order form. More commonly, the ordering process has been simplified by the use of order forms designed specifically for PN. These standardized order forms promote education of practitioners by providing brief guidelines for initiating PN and foster cost-efficient nutrition support by minimizing errors in ordering, compounding, and administration.39 Standardized order forms also may include options for ordering certain related procedures, laboratory tests, protocols for patient management, or consultations with other medical services related to the patient’s nutrition support. Standardized forms and protocols should be reviewed and updated periodically to reflect changes in the practices and patient population of a practice setting and advances in technology that may affect provision of nutrition support.
Adult Parenteral Nutrition Solutions
In general, there are two methods for ordering adult PN. The “standard formula approach” offers a variety of base formulations with a fixed nonprotein-calorie-to-nitrogen ratio. This method usually includes different formulas designed for mild to moderately stressed patients, renal failure patients, fluid-restricted patients, and liver failure patients. Because the nonprotein-calorie-to-nitrogen ratio is fixed, the daily amount of nutrient delivered depends solely on the volume infused. Standard institutional PN formulations may be compounded; however, standardized commercial PN products or “premixed” solutions are available from manufacturers.61 Use of a standard institutional formula may promote clinician prescribing of a complete, balanced formulation. Their use may also promote consistent provision of stable, compatible admixtures. However, efficiencies associated with use of the standard formula approach may be hindered if there is a frequent need to modify the PN formulation. Finally, standard PN formulations may be difficult to use in potentially complicated patients, such as neonatal or pediatric patients, and those with severe malnutrition, organ failure, glucose intolerance, large GI losses, or critical illness.61
The “individualized formula approach” permits compounding of patient-specific solutions. Compounding of the PN solution is limited only by the concentrations of stock solutions and stability of the additives. The nutrient amount delivered depends on the daily volume of the PN solution infused and the nutrient amounts in the PN solution. The total daily amount of PN solution may be prepared in multiple bags or more cost effectively in a single container.39
Traditionally, adult PN solutions have been ordered by expressing the final concentrations of each component in the solution. For example, CAA and dextrose are ordered commonly in final percentage, electrolytes in milliequivalents per liter, and other additives in amount (milliliters or units) per day. This inconsistency may promote confusion and misinterpretation of PN solution contents that may result in harm, especially when patients are transferred between health system environments. To ensure that PN labels in all health system environments clearly and accurately reflect the PN solution contents, guidelines for standardized adult PN labeling have been recommended.39 In addition to including a variety of other information on the label such as dosing weight and administration route, the guidelines recommend expressing PN ingredients in amounts per total volume, which minimizes the need for pharmaceutical calculations to determine the nutrient value of the admixture. Computer software for calculating PN solutions is widely available, and several programs have adapted the recommended labeling guidelines. Pharmaceutical calculations of a two-in-one PN regimen are briefly reviewed (Fig. 119-1).
FIGURE 119-1 Calculation of an adult parenteral nutrition (PN) regimen. To convert to energy units of kilojoules (kJ) multiply values with kilocalories as the numerator (kcal, kcal/mL, kcal/kg, kcal/g) by 4.18 to give the corresponding value in kilojoules (kJ, kJ/mL, kJ/kg, kJ/g).
Several guidelines or clinical rules of thumb are available to help simplify calculation of a PN regimen after a patient’s nutritional requirements have been decided. For example, adult patients receiving only PN therapy may need larger volumes of fluid to provide maintenance requirements and replace extrarenal losses. However, patients requiring other IV drug therapy may receive adequate fluid from an additional IV maintenance solution (e.g., 0.45% NaCl in 5% dextrose) or piggybacked medications (or both). Depending on individual institutional practices, maximally concentrating the PN solution and using an inexpensive maintenance fluid to manage hydration may provide a cost-effective regimen that requires fewer adjustments. Another guideline that may be helpful in designing a PN regimen is to allow a volume of approximately 100 to 150 mL/L of base solution (approximately 200–300 mL/day) for electrolytes and other additives. PN regimens for patients who require very small amounts of additives, such as patients with renal failure, may be further concentrated.
Pediatric Parenteral Nutrition Solutions
Pediatric PN solutions are typically ordered using an individualized approach because clinical practice guidelines often recommend nutrient intakes based on the patient’s weight. To simplify pediatric PN ordering, many institutions use a pediatric-specific PN order form that expresses daily nutrient amount based on weight. For example, protein and fat are ordered as grams per kilogram per day, dextrose as milligrams per kilogram per minute, and electrolytes as milliequivalents per kilogram per day. However, some institutions may order macronutrients by expressing the final concentration of each component in the solution. Current safe practice guidelines suggest that the pediatric PN label identify components as an “amount per day” with a secondary expression of components as “amount per kilogram per day.”39Auxiliary labels may be needed when the format between PN ordering and PN labeling is different. Calculations for determining a pediatric PN solution are reviewed to illustrate fundamental concepts for ordering pediatric PN solutions (Fig. 119-2). Additional features of the pediatric PN label include the dosing weight, administration date and time, expiration date, infusion rate, and duration of infusion. Because infants and children generally receive daily maintenance fluid from the PN regimen, supplemental IV solutions are rarely needed. Pediatric PN may be provided as a two-in-one or TNA formulation. However, the TNA system is not recommended for compounding neonatal and infant PN because of IVFE instability with the often needed higher calcium and phosphorus concentrations.39 The IVFE labeling guidelines for pediatric PN are similar to adult IVFE labeling recommendations.
FIGURE 119-2 Calculation of a pediatric parenteral nutrition (PN) regimen. To convert to energy units of kilojoules, multiply values with kcal as the numerator (kcal, kcal/mL, kcal/kg, kcal/g) by 4.18 to give the corresponding value in kilojoules (kJ, kJ/mL, kJ/kg, kJ/g).
Parenteral nutrition solutions should be administered with an infusion pump. The IV administration line for CAA-dextrose solutions should include a 0.22-μm inline filter to remove particulate matter, air, and any microorganisms that may be present in the solution. IVFEs administered separately from the CAA-dextrose solution must be infused into the PN line by utilizing a y-site port beyond the inline filter because the average size of IVFE particles is approximately 0.5 μm.39 The FDA recommends use of a 1.2-μm filter with TNA solutions, which may be effective in preventing catheter occlusion caused by precipitates or lipid aggregates.39 This filter size is also reported to remove Candida albicans.
INITIATING AND ADVANCING THE PARENTERAL NUTRITION INFUSION
Adult Parenteral Nutrition
The patient’s nutrition status, current clinical status, history of glucose tolerance, and dextrose concentration in the formula will dictate the infusion rate at which the adult PN solution should be initiated. Stable patients with normal organ function and stable baseline serum glucose concentrations have demonstrated minimal effect on serum glucose concentrations when abruptly initiating or discontinuing PN therapy.62,63 However, another approach is to begin the PN infusion and increase the rate gradually over 12 to 24 hours to the desired rate. The infusion rate is likewise reduced in a stepwise fashion, such as decreasing the rate by 50% for 1 hour before discontinuation, when the PN therapy ends.62 This approach should prevent development of hyperglycemia and rebound hypoglycemia, respectively. Alternatively, the PN regimen may be initiated at the goal infusion rate but with a hypocaloric dextrose dose. The dextrose dose can be increased daily to the goal based on patient response. Tapered initiation and cessation should be considered for patients receiving intermittent subcutaneous regular insulin; patients with severe renal or hepatic disease; and patients with other disease states that may increase the risk for development of hyperglycemia or hypoglycemia, such as severe diabetes or pancreatic malignancy.
Although the IVFE dose should not exceed 2.5 g/kg per day or 60% of total daily calories, lower doses of 1 g/kg per day not to exceed 30% of calories have been recommended to minimize negative effects associated with long-chain fatty acids.39 Manufacturer’s information recommends IVFE infusion over 4 to 8 hours for adults. However, infusion over 12 to 24 hours appears to be the best clinical strategy to promote IVFE clearance and minimize risk of negative effects on pulmonary and immune function.39,40
The manufacturer’s guidelines recommend initiating IVFE for adults with a test dose of 0.5 to 1 mL/min for the first 15 to 30 minutes because of the potential for an immediate hypersensitivity reaction. For most patients, this is probably not necessary because of the relatively low incidence and benign nature of acute adverse reactions. In addition, infusion over 12 to 24 hours eliminates the need for a test dose because the infusion rate is within the range of the test dose rates recommended by the manufacturer. Appropriate electrolytes should be provided to patients with normal organ function based on standard nutrient ranges.39 Adjustments may be necessary depending on the patient’s clinical condition. Adults and children older than 11 years of age should receive daily amounts of trace elements and an adult vitamin formulation.
Pediatric Parenteral Nutrition
Pediatric PN solutions are typically initiated with a volume calculated to provide the patient’s daily maintenance fluid requirements on the first day of therapy. Individual substrates are then advanced daily as tolerated with the goal PN regimen generally being achieved by day 3 of therapy. PN should be initiated with the goal protein dose. The initial dextrose dose for older infants and children is based on previous glucose tolerance. Although practices may vary, one approach is to start with 10% dextrose and advance the concentration in 5% increments daily as tolerated to goals of 8 to 12 mg/kg/min in infants, 8 to 10 mg/kg/min in children, or 5 to 6 mg/kg/min in adolescents.16 Initial dextrose doses for premature infants should approximate fetal nutrient delivery rates of 5 to 6 mg/kg per minute. Frequently, this mathematically translates into a final concentration range of 5% to 10% dextrose. The dextrose concentration for the neonatal PN should be advanced daily by 1% to 2.5% or by 2 to 4 mg/kg/min increments to a goal of 8 to 12 mg/kg/min (maximum, 14–18 mg/kg/min).16 IVFE is usually initiated at 0.5 g/kg/day for neonates and 0.5 to 1 g/kg/day for older children and increased daily by 0.5 to 1 g/kg/day. Incremental increases of IVFE dose allow daily serum triglyceride evaluation and early detection of those with impaired fat clearance. The IVFE dose should not exceed 60% of total daily calories for neonates and 30% of total calories for children, and the maximum IVFE dose should not exceed 3 g/kg/day (∼30 kcal/kg/day [126 kJ/kg/day]) for infants and children.37 The best clinical strategy for minimizing the risk of adverse effects associated with rapid IVFE administration and promoting IVFE clearance is to infuse IVFE over 20 to 24 hours or at a rate of 0.15 g/kg/h.37,40 This slow infusion also eliminates the need for a test dose because the infusion rate is less than the test-dose rate recommended by the manufacturer.
IV electrolytes, vitamins, and trace elements should be initiated on the first day of therapy and continued as a daily component of the PN solution.39 Children younger than age 11 years should receive a vitamin product formulated for pediatric patients. Two multivitamin dosing schemas have been suggested for infants and children.39 One method recommends 2 mL/kg/day for infants weighing less than 2.5 kg (<5.5 lb) and 5 mL/day for infants and children weighing 2.5 kg (5.5 lb) or greater. The other suggests 30% of a vial (1.5 mL/day) for infants weighing less than 1 kg (<2.2 lb), 65% of a vial (3.25 mL/day) for infants weighing 1 to 3 kg (2.2–6.6 lb), and 100% of the vial (5 mL/day) for children weighing more than 3 kg (6.6 lb) (up to 11 years of age). Adult IV vitamin formulations should not be used for infants because of potential neurotoxicity from accumulation of polysorbate and propylene glycol preservatives. Weight-based dosage recommendations for pediatric multiple trace element formulations are 0.3 mL/kg for children weighing less than 3 kg (<6.6 lb) and 0.2 mL/kg for children weighing 3 kg (6.6 lb) or greater (maximum, 5 mL/day). Children weighing more than 25 kg (55 lb) should receive an adult trace element formulation. Weight-based doses of the multiple trace element formulations do not provide the recommended daily intake for all trace elements, so additional supplementation or individual dosing with single-entity products may be necessary. Individualized dosing allows for dose adjustment based on serum trace element assessment, individual patient characteristics (e.g., cholestasis, stool losses, wounds), and the need to minimize administration of trace elements that accumulate in patients receiving chronic PN such as chromium and manganese. Pediatric patients receiving PN commonly transition from PN support to enteral nutrition by gradually, over a period of days to weeks, decreasing the PN infusion rate while increasing the enteral intake. The PN infusion rate should be reduced for 1 to 2 hours before stopping the infusion for neonates and infants because of their immature counter-regulatory mechanisms that contribute to an increased risk for developing rebound hypoglycemia.14 Blood glucose concentrations should be checked within 15 to 60 minutes after the PN infusion ends.
Continuous versus Cyclic Infusions
Use of continuous infusions is attractive for patients with unstable fluid balance or glucose control. The intermittent or cyclic infusion of PN over a period of time less than 24 hours, usually for 12 to 18 hours each day, is useful for hospitalized patients with limited venous access in whom administration of multiple other medications requires interruption of the PN infusion.62 Cyclic PN also may prevent or treat hepatotoxicities associated with continuous PN therapy. In addition, this delivery mode allows patients receiving PN at home the ability to resume a relatively normal lifestyle.62 Various protocols have been reported that suggest incremental increases to the maximum infusion rate for a desired period of time followed by a gradual taper to discontinue the solution.14,62 However, metabolically stable adults and older children (older than age 2 years) receiving fat-based PN regimens are likely candidates for abrupt initiation and discontinuation of their intermittent PN regimen.14,62–64 Cyclic PN is not optimal for all patients and should be used with caution for those with severe glucose intolerance, diabetes, or unstable fluid balance.
EVALUATION OF THERAPEUTIC OUTCOMES
Thorough and consistent monitoring of patients who are receiving PN is necessary to ensure that the desired nutritional outcomes are achieved and to prevent the occurrence of adverse effects or complications. Routine evaluation should include the assessment of the patient’s clinical condition with a focus on nutritional and metabolic effects of the PN regimen. Serial documentation of a patient’s response to a particular regimen is a helpful guide for determining appropriate adjustments in fluid, electrolyte, and nutrient therapies.
Several biochemical and clinical measurements are necessary for effective monitoring of patients receiving PN. Serum concentrations of electrolytes, hematologic indices, and biochemical markers for renal function, liver function, and nutrition status should be measured before PN initiation and periodically thereafter depending on the patient’s age, nutrition status, and clinical condition. The frequency of blood laboratory measurements for neonates and infants tends to be more conservative because of their smaller circulating blood volumes and, in some cases, lack of central vascular access. Other important clinical measurements include vital signs, weight, total fluid intake and losses, and nutritional intakes. Weekly measurements of height, length, and head circumference are helpful for monitoring nutritional changes in neonates. Monitoring parameters considered important for patients receiving PN; the suggested frequency of measurement for each are outlined in Figure 119-3. Appropriate assessment and evaluation of patient data can identify potential complications that may be avoided or treated early. Monitoring protocols should be developed and tailored for the patient population, medical practices, and resources of individual practice settings.
FIGURE 119-3 Monitoring strategy for patients receiving parenteral nutrition (PN).
COMPOUNDING, STORAGE, AND INFECTION CONTROL
The United States Pharmacopeia (USP) Chapter 797 details the procedures and requirements for compounding sterile preparations, including PN formulations.65 These standards apply to all healthcare settings in which sterile preparations are compounded and are used by boards of pharmacy, the FDA, and accreditation organizations such as The Joint Commission. Compounded sterile preparations are defined by risk level (immediate use, low, low with 12-hour beyond-use date, medium, and high) based on the probability of microbial, chemical, or physical contamination. PN solutions are classified as a medium-risk compounded sterile preparation. In general, PN solutions should be prepared using aseptic technique in a device or room that meets International Organization for Standardization (ISO) class 5 standards that is located in an ISO class 7 buffer area with an ISO class 8 ante area.65 Personnel must be trained adequately for personnel cleansing and garbing procedures and aseptic manipulations. Supervision by a pharmacist experienced in compounding IV solutions and knowledgeable about the stability, compatibility, and storage of PN solutions is necessary. Quality assurance procedures should be developed to maintain safe and accurate admixture preparation. A standardized process for PN ordering, labeling, determining nutrient requirements, screening of the PN order, PN administration, and monitoring has been recommended to minimize risk of potentially life-threatening compounding errors.39,61,66 The potential risk of infectious complications associated with PN solution contamination can be decreased greatly when pharmacy-based admixture programs follow specific guidelines developed to ensure proper compounding of PN solutions.65
In general, the type of solution being prepared dictates the methods of compounding, storage, and infusion. Currently, the two most commonly used types of PN solutions are two-in-one solutions with or without IVFE piggybacked into the PN line and TNAs. Methods for compounding PN solutions vary based on a healthcare system’s patient population and medical practices and the number of PN solutions that need to be prepared. PN base solutions may be prepared by using gravity-driven transfer of CAA stock solutions to partially filled bags of concentrated dextrose stock solutions.39,67 Other practice settings may use standardized commercial PN products with CAA and dextrose separated within a single bag that must be mixed before use.39,61 Advances in compounding technology have facilitated the use of automated compounders for preparing PN solutions. Automated compounders are computer-based systems that perform the calculations necessary to determine volumes of nutrient stock solutions for PN formulations. In addition, most automated compounder systems include software that communicates the determined calculations directly to a transfer pump device that delivers fluid from the source container to the final container by either a volumetric or gravimetric fluid pumping system.67 Advantages associated with automated compounders include reduced personnel time and compounding materials and improved compounding accuracy. Disadvantages include the potential for equipment failure and power outages.
Assurance of solution sterility during compounding, storage, and administration is necessary to reduce the risk of infection and related complications. Because of their acidic pH and hypertonicity, two-in-one PN formulations are poor media for microbial growth.39,68 However, several characteristics of IVFE, such as isoosmotic tonicity, near neutral to alkaline pH, and glycerol content favor microbial growth, particularly at room temperature.39 When IVFEs are added to dextrose-CAA solutions to make TNAs, the growth potential is decreased, presumably because of the protective effects of the hypertonic dextrose-CAA solution and decreased pH.69
CAA-dextrose solutions generally are stable for 30 days if refrigerated at 4°C (39°F) and protected from light.24 However, because of the risk for microbial contamination, manufacturers recommend storage of PN solutions for as little time as possible after preparation. The USP 797 standards recommend storage times of not more than 30 hours at controlled room temperature (20°–25°C [68°–77°F]) and not more than 9 days at cold temperatures (2°–8°C [36°–46°F]) for all medium-risk compounded sterile preparations, including PN solutions.65
Because IVFEs support growth of gram-positive and gram-negative bacteria as well as fungi, the appropriate hang time for IVFE has been largely debated. Some recommend that infusion time for IVFE administered as a separate infusion should not exceed 12 hours and infusion time for IVFE administered as a component of TNA should not exceed 24 hrs.39 The Centers for Disease Control and Prevention (CDC) guidelines do not address infusion times for IVFE.59 Instead, the guidelines recommend IV tubing replacement every 24 hours for both IVFE infused separately or when given as part of a TNA. IV tubing used continuously for infusion of IV solutions other than blood, blood products, or IVFE should be changed no more frequently than at 96-hour intervals but at least every 7 days.59 Compliance with recommendations for safe IVFE administration to pediatric patients is challenging. First, the maximum recommended rate of IVFE infusion for infants typically requires an infusion time longer than 12 hours, the recommended infusion time to minimize the risk of IVFE contamination. For example, an infant receiving the maximum recommended IVFE dose (3 g/kg/day) at the maximum recommended rate of 0.15 g/kg/h would require at least a 20-hour infusion.37 Some institutions attempt to comply with a 12-hour hang time by dividing the daily dose into two unit volumes and infusing them over 12 hours each. Second, commercially available IVFE products are not manufactured in unit volumes consistent with the daily volumes usually prescribed to infants, which may be as low as 2 mL/day. Infants receiving unit volumes larger than those prescribed are at risk for adverse events associated with IVFE infusion–related errors.41 Finally, use of TNA formulations, which would allow IVFE infusion over 24 hours with decreased contamination risk, are not an option because they are not recommended for neonates and infants.39 Because of these reasons, some institutions aseptically transfer IVFE into plastic syringes for syringe pump infusion to improve safety and to comply with IVFE administration rate recommendations.41,69 Use of repackaged IVFE preparations, however, has been associated with increased risk of contamination during compounding or infusion because of IV line manipulation.69 There are no consistent recommendations for an acceptable infusion time of repackaged IVFE preparations for non-TNA use. In fact, the CDC recommendations do not address use of repackaged IVFE preparations.59 Given the well-documented risk of microbial contamination with IVFE manipulation, however, a 12-hour maximum infusion time for repackaged IVFE seems prudent.
Repackaging IVFE before administration to neonates and infants has been heavily debated. Although some clinicians maintain that the benefits of cost effectiveness and increased patient safety with administering smaller IVFE units outweigh the risks of microbial contamination, others clinicians continue to advocate for the delivery of IVFE direct from the manufacturer’s container to decrease infection risk.
Stability and Compatibility
Comprehensive current information regarding compatibility and stability of PN solutions can be found in several reference sources such as Handbook on Injectable Drugs68 and King Guide to Parenteral Admixtures.70 In many cases, the answer to a compatibility question may not be readily available, and a review of the primary literature may be necessary. When information is not available, clinical judgment and experience must be used carefully to resolve the situation.
The stability of a PN formulation is determined by the rate or degree of component degradation and any resulting changes in chemical integrity or pharmacologic activity that may render the formulation unsuitable for safe administration. In general, the sterile combination of PN components accelerates the rate of physicochemical destabilization of all of the components in the formulation; certain amino acids, vitamins, and IVFE are the most susceptible nutrients.39 When compounded and stored appropriately, the degree of degradation is usually not clinically relevant for most patients receiving short-term PN because many patients have sufficient stores of those susceptible nutrients to support any short-term periods of suboptimal intake, thereby minimizing the risk of clinical symptoms of deficiency. However, nutrient degradation that is more extensive may be problematic for patients with marginal nutrient stores who receive long-term PN. TNAs present additional stability challenges because of the presence of IVFE in the solution. IVFE stability in TNAs is affected by amino acid and dextrose concentration, solution pH, order of mixing, electrolyte amounts, and final TNA volume as well as container material, storage conditions, and addition of nonnutrient drugs. Stability studies on the effect of specific electrolyte concentrations on TNA stability are limited. In general, IVFE stability is affected by the PN cation content. Divalent and trivalent cation additives such as calcium and magnesium have a greater destabilizing potential compared with monovalent cation additives such as sodium and potassium. However, when given in sufficiently high concentrations, monovalent cation additives may also produce instability. Cations act to reduce the surface potential of the emulsion droplet, thereby enhancing tendency to aggregate and ultimately, in some cases, destabilize the solution to coalescence or a “cracked” admixture.24,39,71 When a cracked IVFE occurs, the oil phase separates from the water phase, resulting in the appearance of free oil fat globules. Early stages may appear as subtle changes in the uniformly white appearance of the TNA, which may progress to yellow oil streaks throughout the bag or development of an amber oil layer at the top of the admixture bag. TNA formulations with any visible free oil should be considered unsafe for parenteral administration because infusion of circulating fat globules may be of sufficient size to accumulate in the pulmonary vasculature and potentially compromise respiratory function. In general, the likelihood of preparing an unstable TNA formulation can be minimized by maintaining the final concentrations of CAA greater than 4%, dextrose greater than 10%, and IVFE greater than 2%.71 Specific guidelines for compounding TNA formulations are reviewed elsewhere.24
Because of differences in pH among various CAA products and in phospholipid content among IVFE products, the manufacturer of each product should be consulted for compatibility and stability information before routine mixing of components. One approach to compounding TNA formulations manually is to first combine CAA, dextrose, and sterile water (if necessary). Electrolytes, vitamins, and trace elements are added, and then the solution is visually inspected for precipitate or other particulates. Finally, IVFE is added, and the solution is visually inspected to ensure a uniform emulsion exists.24,42 However, mixing components in this specific order and time sequence may not be possible with the use of automated compounders. Although CAA, dextrose, and IVFE may be simultaneously transferred to an admixture container, the compounder’s manufacturer should be consulted for the optimal mixing sequence to ensure safe compounding of TNA solutions.
The precipitation of calcium and phosphorus is a common interaction that is potentially life-threatening.24,39,72 Factors that enhance the risk of precipitate formation include high concentrations of calcium and phosphorus salts, use of the chloride salt of calcium, decreased amino acid and dextrose concentrations, increased solution temperature, increased solution pH, use of an improper sequence when mixing calcium and phosphorus salts, and the presence of other additives (including IVFEs).24,39,72 In general, steps to minimize risk of calcium and phosphate precipitation in PN formulations include the use of calcium gluconate instead of calcium chloride because it is less reactive, adding phosphate salts early in the mixing sequence, adding calcium last or nearly last, and agitating the mixture throughout the admixture process to achieve homogeneity. PN formulations with a lower final pH should be used when clinically appropriate. Higher final concentrations of dextrose and CAA and lower final concentrations of IVFE favor a lower admixture pH. CAA product-specific solubility curves that are available from the manufacturer or primary literature should be used for determining solubility. Use of a calculation to derive a sum or product of calcium and phosphate concentrations should not be used as the sole criterion for determining solubility because products of calcium and phosphate concentrations vary inconsistently as calcium concentration decreases and phosphate concentration increases.72
Electrolyte stability in TNA solutions is difficult to assess because of poor visualization of a precipitate if one occurs. PN solutions for neonates and infants tend to have larger calcium and phosphorus amounts, as well as other divalent cations, that limit the use of TNA formulations. Because of the relatively limited amount of published stability information, the use of a two-in-one formulation with separate administration of IVFEs is recommended for neonates and infants.39 In general, alternative methods of delivering electrolytes or other medications should be pursued in any clinical situation in which compatibility information involving a TNA solution is lacking. Because the addition of bicarbonate to acidic PN solutions may result in the formation of carbon dioxide gas and insoluble calcium and magnesium carbonates, sodium bicarbonate use in PN solutions is not recommended.39 Use of a bicarbonate precursor salt such as acetate usually is preferred.
Vitamins may be affected adversely by changes in solution pH, presence of other additives, storage time, solution temperature, and exposure to light.24 Because of variable stabilities of individual vitamins, IV vitamin solutions should be added to the PN solution as near to the time of administration as is clinically feasible and should not be in the PN solution longer than 24 hours.
Increased peroxide concentrations have been reported in IVFE and dextrose–amino acid solutions after addition of IV multivitamins or exposure to air or light.73 Multiple in vitro experiments have reported negative effects of peroxides and associated metabolites on organ and immune function. Peroxides are associated with neonatal hypoxic–ischemic encephalopathy, intraventricular hemorrhage, periventricular leukomalacia, chronic lung disease, retinopathy of prematurity, and necrotizing enterocolitis.73 Neonates and infants are at increased risk for harmful effects of peroxides because they receive a higher daily peroxide load from PN solutions and they have lower endogenous antioxidant levels. Protecting PN and IVFE solutions from light is therefore recommended to minimize peroxide formation.73
Many patients receiving PN also receive other IV medications. The compatibility of these medications and other IV solutions is an important concern. Although some medications may be added directly to the PN solution and administered at the same rate as the PN infusion, most are administered as a separate admixture piggybacked in the PN line. Several criteria should be considered before medications are added directly to the PN solution because of the potential for ineffective drug therapy or other complications associated with physiochemical incompatibility and stability of the PN solution.39 First, the drug should be stable for at least 24 hours and should have pharmacokinetic properties appropriate for continuous infusion. Second, there should be documented chemical and physical compatibility of the medication with PN mixture components and other medications that may be piggybacked concomitantly into the PN line. Advantages of using PN admixtures as drug vehicles include consolidation of dosage units, improved pharmacodynamics for certain drugs, conservation of fluid in volume-restricted patients, fewer venous catheter violations, and decreased compounding and administration times. However, a major disadvantage to the use of PN solutions as drug-delivery vehicles is the lack of compatibility and stability data for the PN solutions that are used commonly in clinical practice. Medications frequently added to PN solutions include regular insulin and histamine-2 receptor antagonists.39,68,70
COMPLICATIONS OF PARENTERAL NUTRITION
Mechanical and Technical Complications
Mechanical and technical complications include malfunctions in the system used for IV delivery of the solution, such as infusion pump failure, problems with administration sets or tubing, and problems with the catheter. Although problems associated with infusion pumps and administration sets can be decreased by appropriate equipment selection and routine care and monitoring, catheter-related complications are potentially life-threatening. Pneumothorax, catheter misdirection or migration into the wrong vein or improperly positioned within the cardiac chambers, arterial puncture, bleeding, and hematoma formation may occur during surgical placement of the catheter. Many of these complications, in addition to venous thrombosis and air embolism, can occur after insertion. Catheters occasionally occlude or break during use. If these problems cannot be rectified easily, the catheter may need to be surgically replaced.
Infectious complications can be a major hazard for patients receiving CPN because of the increased risk associated with the presence of an indwelling CVC. The source of a CVC infection may be skin organisms at the catheter insertion site, contamination of the catheter hub, or hematogenous seeding of the catheter from a distant site. In addition, patients receiving PN therapy are often predisposed to infection because of compromised immunity or concomitant infection. Frequent use of broad-spectrum antibiotic therapy and malnutrition are also predisposing factors for development of infection. The risk of catheter infection is increased for those who require multiple manipulations of the line used for PN administration. The risks for infection are also increased for those who experience failure of in-line bacterial filter, poor catheter placement technique, and poor CVC and insertion site care.59
Infection rarely develops secondary to solution contamination.59,74 Strict adherence to protocols for preparation of PN solutions should minimize this occurrence.39,65 Catheter-related bloodstream infections (CRBSIs), defined as the presence of clinical manifestations of infection (e.g., fever, chills, hypotension) associated with bacteremia or fungemia resulting from no apparent source other than the catheter, are common sources of systemic infection.74Before this diagnosis can be made, there should be evidence of more than one positive blood culture result obtained from the peripheral vein with growth of the same organism from a blood culture obtained from the catheter or catheter segment. When a CRBSI is suspected or confirmed, appropriate antimicrobial therapy is initiated. Retention or removal of the central catheter depends on the patient’s severity of illness, the suspected or identified pathogen, and the type of catheter involved. The catheter may be removed and replaced in the same site, the catheter may be removed and replaced at a different anatomic location, or it may not be replaced.74 Filling the catheter with antimicrobials such as vancomycin or antiseptics such as 70% alcohol and allowing the solution to dwell for a period of time while the catheter is not in use is referred to as a catheter lock.59 Antimicrobial catheter locks have been used to prevent and treat CRBSI in patients with long-term catheters such as those receiving home PN.59,75 Specific guidelines for treatment of CRSBI have been recently reviewed.74
Ethanol catheter lock therapy has offered promise for the prevention and treatment of CRBSI. The best method for ethanol removal from the CVC after ethanol catheter lock is not known. If the ethanol is withdrawn from the CVC, blood is introduced into the CVC, which may increase the risk of biofilm formation. Alternatively, clearing the catheter by flushing the ethanol into the patient is concerning because the safe amount of ethanol to routinely infuse into patients, particularly neonates and infants, is not known.
Metabolic and Nutritional Complications
Metabolic and nutritional complications associated with PN therapy are numerous; frequently multifactorial in origin; and if left untreated, potentially fatal. Metabolic abnormalities related to substrate intolerance, fluid and electrolyte disorders, and acid–base disorders are summarized in multiple review articles.32,33,38,39,56,62
Parenteral Nutrition–Associated Liver Disease
Parenteral nutrition–associated liver disease as evidenced by elevations in total bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase is well documented.33,76 No single etiology has been identified, although several risk factors have been reported. Risk factors for children include degree of prematurity, sepsis, hypoxia, lack of enteral nutrition, small bowel bacterial overgrowth, GI conditions requiring surgical intervention, duration of PN therapy, and long-term administration of excessive calories.33,76,77 PNALD in infants is characterized clinically by a serum direct bilirubin concentration greater than 2 mg/dL (>34.2 μmol/L).33 Taurine deficiency has been proposed as an etiology of cholestasis for preterm infants and neonates.33,76 Taurine is a conditionally essential amino acid that is not present in standard CAA solutions but is important for neonatal and infant bile metabolism. However, the effectiveness of PN regimens with CAA solutions containing supplemental taurine is unclear. Recent studies have focused on the potential relationship between IVFE and the development of PNALD.45 Soybean oil–based IVFEs contain large concentrations of plant sterols or phytosterols, which are inefficiently metabolized to bile acids by the liver. Experimental data suggest parenteral phytosterols may impair bile flow. Improvement or reversal of PNALD has been reported for patients who received a fish oil–based IVFE that is not currently commercially available in the United States.45 Other PNALD treatments that have been investigated include providing reduced doses of soybean oil–based IVFE and use of enteral fish oil in patients with limited oral intake.78
Risk factors for PNALD in adults include preexisting liver diseases, sepsis, preexisting malnutrition, extensive bowel resection, prolonged duration of PN therapy, lack of enteral intake, nutrient deficiencies such as choline deficiency, and long-term administration of excessive calories.33,76 PNALD in adults typically presents as steatosis and steatohepatitis on biopsy. Clinically, PNALD is characterized by mild elevations in serum liver enzymes, usually less than three times the upper limit of normal, with peak enzyme levels usually occurring between 1 and 4 weeks after initiating PN. In many cases, the liver abnormalities improve or resolve with manipulation of substrate intake or discontinuation of PN therapy. However, in severe cases, liver dysfunction may progress to overt failure and death despite use of traditional therapies such as using cyclic PN, ursodiol, and oral antibiotics for bacterial overgrowth; maximizing enteral feeding; and avoiding sepsis and parenteral overfeeding.33,76 Intestinal transplant with or without liver transplantation has become a treatment option for PN-dependent patients who have progressive PNALD.
Hypertriglyceridemia, defined as serum triglyceride concentrations greater than 400 mg/dL (>4.52 mmol/L) for adults and 150 mg/dL (1.70 mmol/L) to 200 mg/dL (2.26 mmol/L) for preterm infants, neonates, and older pediatric patients, may occur for patients receiving IVFE-based PN. Risk factors include preexisting liver or pancreatic dysfunction, sepsis, multiple-organ failure, degree of prematurity, IVFE infusion rate, and dose.39,40
IVFE–associated hypertriglyceridemia is generally thought to be caused by defective lipid clearance or an excessive rate of IVFE administration.37,39 Premature infants and neonates have relatively slower lipid clearance than do adults because of immature metabolic pathways, including decreased lipoprotein lipase activity.37,40 Reducing the IVFE infusion rate or dose or withholding IVFE therapy should be considered when patients present with hypertriglyceridemia or lipemic serum.37,39 Use of low-dose heparin (1 unit/mL of two-in-one PN formulation) to stimulate lipoprotein lipase activity has been suggested as a potential therapeutic intervention to treat IVFE-associated hypertriglyceridemia in neonates.14,37 However, others have suggested that the risk associated with heparin delivery via PN outweighs the clinical benefits because of the potential for compounding errors associated with heparin and insulin confusion.79 The role of carnitine for treatment of IVFE-associated hypertriglyceridemia is not clear.14,37
Hyperglycemia is one of the most common complications associated with PN administration and is associated with a history of diabetes, metabolic stress, adverse effects of medications such as glucocorticoids, and excessive carbohydrate administration. In the pediatric population, additional risks for hyperglycemia include prematurity and surgery. The optimal blood glucose concentration for acutely ill hospitalized patients receiving PN is not known. However, a target range of 140 to 180 mg/dL (7.8–10 mmol/L) has been suggested for adults, and less than 150 mg/dL (8.3 mmol/L) has been suggested for neonates.80,81 Clinical management of PN patients with hyperglycemia has not been well studied and is largely empiric. Blood glucose concentrations can be controlled with regular insulin, which may be given subcutaneously or added to the PN formulation. One approach for adult PN patients requiring insulin or oral hypoglycemic agents before starting PN therapy is to initiate PN with approximately 100 to 200 g of dextrose and add 0.05 to 0.1 units of regular insulin per gram of dextrose in the PN solution for those patients with mild hyperglycemia (130–150 mg/dL [7.2–8.3 mmol/L]). The insulin dose may be increased to 0.15 to 0.2 units per gram of dextrose for patients with moderate hyperglycemia (151–200 mg/dL [8.4–11.1 mmol/L]).39,82 Blood glucose concentrations should be monitored every 4 to 6 hours. Blood glucose measurements above the goal range should be treated with regular insulin administered subcutaneously according to an appropriate sliding scale. The insulin dose is modified daily by adding 60% to 100% of the sliding-scale insulin given over the previous 24 hours to the PN formulation daily until blood glucose concentrations are stable and within the target range. When blood glucose measurements are stable, the dextrose dose may be advanced. The frequency of monitoring blood glucose concentrations may be decreased after blood glucose concentrations are stable within the target range at the goal dextrose dose. Use of a separate IV insulin infusion is most commonly used for pediatric patients, but it may also provide better and safer glycemic control for patients with very large insulin requirements or unstable marked fluctuations in their blood glucose concentrations.
Severe and rapid declines in serum phosphate, potassium, and magnesium concentrations; fluid retention; and other micronutrient deficiencies are common features of the refeeding syndrome.83,84 Individuals at risk for refeeding syndrome include those who are severely malnourished with significant weight loss and who receive aggressive nutritional supplementation. Other examples of patients receiving PN therapy who may be at risk for developing refeeding syndrome abnormalities include those who are unfed for 7 to 10 days with evidence of stress or nutritional depletion; those with chronic diseases causing undernutrition such as cancer, cardiac cachexia, chronic obstructive pulmonary disease, or cirrhosis; and individuals who were previously morbidly obese and have experienced massive weight loss.84 The mechanism of the electrolyte abnormalities appears to be related to acute provision of macronutrient substrates that promote anabolism in an environment of depleted total body stores of phosphorus, potassium, and magnesium. Recommendations for initiating PN in adults at risk for refeeding syndrome include providing 25% to 50% of the calculated nonprotein caloric requirements initially. The dextrose dose should be initiated at approximately 100 to 200 g/day. Calories should be advanced over 3 to 4 days to the desired goal. Because the metabolic abnormalities described with refeeding syndrome appear to be related primarily to acute provision of large amounts of dextrose, the goal protein dose may be provided with the initial PN infusion. Pediatric PN regimens are usually advanced over several days as a general practice for all pediatric patients. Additional recommendations for minimizing the risk of refeeding syndrome for pediatric patients include provision of additional phosphorus and potassium above standard nutrient requirements at the time PN is initiated.85
Complications Associated with Long-Term Parenteral Nutrition
Other nutritional complications of PN therapy may develop over a prolonged course of therapy (weeks to months) as a result of inappropriate intake of a particular nutrient. Certain conditions, such as metabolic stress in a previously malnourished patient, may elicit symptoms of deficiency much earlier if a nutrient is not appropriately provided. For example, lactic acidosis and other life-threatening complications associated with severe thiamine deficiency have been reported for patients who received PN solutions without multivitamin supplementation.86 Maintenance doses of vitamins, trace elements, and essential fatty acids should be provided to all patients with normal age-related organ function receiving PN.
Essential Fatty Acid Deficiency
Patients receiving PN regimens without IVFEs for extended periods (weeks to months) are at risk for development of EFAD. Clinical signs of EFAD include hair loss, desquamative dermatitis, thrombocytopenia, and malabsorption and diarrhea resulting from changes in intestinal mucosa.38,39 EFAD also may be diagnosed by evaluating plasma fatty acid profiles. Although this assessment is not routinely available, it can be provided by several larger regional labs. A triene-to-tetraene ratio more than 0.4 is biochemical evidence for EFAD. Although the time in which EFAD may develop depends on the patient’s nutrition status, disease state, and age, these manifestations may occur 2 to 4 weeks after initiation of fat-free PN in adults and within 48 hours in newborn infants.38,40
Metabolic Bone Disease
Metabolic bone disease has been reported for adults and children receiving long-term home PN.33 This disorder in adults is characterized by osteomalacia with or without osteoporosis that may present without associated clinical, radiologic, or biochemical abnormalities. The diagnosis may not be made for premature infants until after the development of bone fractures or overt rickets. The etiology is poorly understood and likely multifactorial. Treatment options include pharmacologic intervention, calcium and vitamin D supplementation, and exercise. Because excessive vitamin D has also been implicated in the development of metabolic bone disease, others have recommended removal of vitamin D from the PN for patients with a normal 25-hydroxyvitamin D concentration and low serum parathyroid hormone and 1,25-hydroxyvitamin D concentrations.14,33
Trace Elements and Vitamin Complications
Clinical symptoms of trace element deficiencies, although rare, have been reported for patients receiving PN. More commonly, decreased serum trace element concentrations have been reported in a variety of patient populations. However, the clinical significance of decreased concentrations of many trace elements is not known because serum concentrations often do not correlate with total body stores.47Occasionally, patients may develop clinical toxicities from elevated vitamin or trace element intakes or decreased metabolism. These abnormalities are frequently associated with an underlying disease state such as severe renal or hepatic failure and may necessitate reduction in vitamin and trace element intake.
Many trace elements are present in PN components as contaminants.47 Some investigations of patients with normal organ function who were receiving PN supplemented with commercially available parenteral multiple trace element solutions have reported concern with elevated serum concentrations of trace elements such as chromium and manganese.47,87 Aluminum is a common contaminant of many sterile IV solutions, including those used for compounding PN. Calcium and phosphorus solutions are among those components with higher levels of aluminum contamination.88,89 Aluminum accumulation may occur during long-term PN therapy, especially for patients with renal insufficiency, and is associated with abnormal neurologic and hematologic function and metabolic bone disease in adults and premature infants.33,88,89 Preterm infants are at higher risk of aluminum toxicities because they receive larger doses (micrograms per kilogram) from PN solutions than adults.88 Preterm infants are also more likely to retain aluminum because of immature renal function. Although the maximum safe level of IV aluminum intake is unknown, the FDA has reported that parenteral doses of 4 to 5 mcg/kg/day were associated with central nervous system and bone toxicity for patients with impaired renal function, including premature neonates.90 Even smaller amounts may result in tissue accumulation but no documented toxicity.
Recent data suggest that the aluminum content of sterile solutions used for compounding PN has declined as a result of awareness of toxicity and improvements in industrial PN component preparation.88However, in 2004, the FDA implemented a restriction of aluminum content in large-volume PN stock solutions (CAA, dextrose, sterile water for injection, IVFE) to a maximum of 25 mcg/L and a requirement for manufacturers to indicate the maximum aluminum concentration at expiration for both large- and small-volume parenteral products used for PN.90 Recent investigations of aluminum content in PN component products have reported differences in actual aluminum amounts in stock solutions and expected amounts based on the manufacturer’s label, but measured levels in PN solutions exceed FDA guidelines.89,91 In addition, the aluminum content of PN stock solutions appears to vary considerably during the shelf life of the products and tends to increase with time because of leaching from glass containers. The amount of aluminum contamination delivered to patients receiving long-term parenteral therapy, such as chronic PN patients or dialysis patients, is substantially reduced if newer stock is used for their therapy.89
HOME PARENTERAL NUTRITION
Advances in technology for the delivery of IV solutions have allowed medically stable patients who require extended PN therapy to be maintained indefinitely on IV nutrition. An increasing concern for cost containment of healthcare services has fostered use of sophisticated infusion devices to provide PN at home. Numerous programs are now available outside the traditional healthcare setting to support patients with various long-term or permanent medical conditions. Standards have been developed to promote safe and effective care.92 Home PN services may be coordinated and administered through a hospital or by a commercial home care company.
Many factors are considered in selecting candidates for home PN therapy. Significant benefit must be expected from the therapy. Examples of patients who have been maintained successfully with home PN include those with severe GI dysfunction secondary to Crohn’s disease, ischemic bowel disease, severe GI motility disorders, extensive intestinal obstruction, and congenital bowel dysfunction.93 The patient and the patient’s caregiver must be willing to complete training and assume numerous responsibilities for managing the new daily routine in the home. Other logistics such as funding, procurement of solutions and supplies, and clinical management and followup must be evaluated, resolved, and individualized for each patient in order to achieve the desired outcomes.92
Patients commonly receive PN solutions from the home care provider. IV vitamins or other additives may be added daily by the patient or caregiver, depending on the arrangement with the home care provider. The solution generally is administered through the night by infusion pump over 10 to 12 hours.62 A cycled regimen allows the patient time away from the pump during daylight hours and provides many patients with the freedom to have a reasonably normal daily routine. Clinical management and follow up are performed periodically according to the needs of the patient and the protocol of the home care provider or the managing healthcare team. A coordinated effort among several healthcare professionals, including physicians, pharmacists, nurses, social workers, and the patient and the patient’s caregiver, as well as the suppliers, is paramount to providing safe and effective management. Home PN affords some patients the potential for an ambulatory lifestyle while maintaining an IV feeding regimen that was previously only available in the hospital setting. For others, home PN may contribute to a better quality of life in the comfort of their homes.93
Considerations for individualizing a patient’s PN regimen include goals determined from a patient-specific nutrition assessment, type of available vascular access, and macronutrient and micronutrient requirements. In general, both macronutrient and micronutrient doses are age and weight based but are also affected by degree of metabolic demand, organ function, other drug therapy, exogenous losses, and acid–base status. Nutrient amounts provided by the PN may also require adjustment based on enteral intake either orally or by feeding tube in patients with recovering GI tract function.
Patient-specific caloric goals include (a) adequate energy intake to promote normal growth and development in neonates, infants, and children; (b) energy equilibrium and preservation of fat calorie stores in well-nourished adults; and (c) positive energy balance in malnourished patients with depleted endogenous fat stores. Overweight patients with a body mass index above 30 kg/m2 may require less caloric support than nonobese patients with the same clinical condition.10 Critically ill adults may also benefit from a hypocaloric regimen.10 Specific nitrogen goals are positive nitrogen balance or nitrogen equilibrium and improvement in the serum concentration of visceral protein markers such as transferrin or prealbumin in patients without systemic inflammation. Routine monitoring is necessary to ensure that the nutrition regimen is suitable for a given patient as the patient’s clinical condition changes and to minimize or treat complications. The PN component doses usually require individualized adjustments as the patient’s clinical condition affects further changes in metabolic stress, organ function, fluid and electrolyte balance, and acid–base status.
Appropriate patient selection, assessment, and monitoring are key to successful PN therapy and the prevention of unnecessary complications. Because pharmacists are actively involved in the provision of PN at many levels, including direct patient care, education, and research, nutrition support is recognized as a pharmacy practice specialty.94 In addition, as the interprofessional approach to specialized nutrition support has evolved, standards of practice have been defined for pharmacists as well as for other healthcare professionals who provide nutrition support care.4,7–9 Standardized order forms and monitoring protocols are useful tools to ensure safe administration and monitoring of PN therapy. The future of PN therapy and the role of nutrition-support clinicians will be affected primarily by new insights from clinical research and economic challenges in the healthcare environment.
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