Formula Design - The A.S.P.E.N. Nutrition Support Practice Manual, 2nd Edition

Introduction

I. Formula Design

II. Compatibility Issues III. Stability Issues

IV. Microbial Growth Potential V. Automated Compounding VI. Off-Site Compounding Centers VII. Ordering PN Formulations VIII. Labeling PN Formulations References

I. Formula Design

A. Components of a PN admixture

1. Protein source: Amino acids are included in the PN admixture as the source for new protein synthesis.

a) Crystalline amino acid solutions are classified as either standard or specialized. The standard amino acid solutions contain a balanced or physiologic mixture of essential and nonessen- tial amino acids.¹The base solutions are available in a range of concentrations from 3% to 20%. The specialized amino acid solutions contain mixtures of amino acids designed to meet disease- or age-specific amino acid requirements.

b) Amino acid compositions of commercially available formulations intended for infant use have an amino acid profile that has been demonstrated to result in plasma amino acid levels in the same range as those seen 2 hours postprandial in the breast-fed infant. These specialized amino acid formulations also contain taurine, which is involved in the conjugation of bile acids. Cys- teine can be added separately at the time of preparation. Infant amino acid formulations are more acidic than standard amino acid products.²This acidity enhances calcium and phosphorus solubility and allows higher concentrations of these two nutrients without causing precipitation.

2. Carbohydrate source: Carbohydrate serves as the primary energy substrate in a PN formulation. The patient’s energy requirements and glucose oxidation rate, and the desired balance of carbohydrate and fat calories, determine the amount of carbohydrate in a given PN admixture.

a) Dextrose monohydrate is used almost exclusively in PN solutions as the source of carbohydrate calories. Dextrose monohydrate provides 3.4 kcal/g, and base solutions are available in a range of concentrations, from 5% to 70%.

b) Glycerol is a naturally occurring sugar alcohol that is used as an alternative source of energy in some PN formulations. It yields 4.3 kcal/g and has been shown to be protein sparing when used concomitantly with amino acids.³

3. Fat source: Fat is delivered in the form of stabilized emulsions.

These emulsions provide essential fatty acids and are a concentrated source of calories.

a) Long-chain fatty acid (LCFA) emulsions currently are the only commercially available source of intravenous fat emulsions (IVFE) in the United States. These fat emulsions are made from either soybean oil or a mixture of safflower and soybean oils.^4,5 They are available as concentrations of 10%, 20%, and 30% fat emulsions. IVFE also contain egg phosphatides as an emulsi- fier and glycerol to adjust the osmolarity.

b) Medium-chain fatty acid (MCFA)/LCFA physical mixtures are available in Europe. Two separate triglyceride sources, MCFA and LCFA, are combined to create these mixtures.

MCFA/LCFA mixtures take advantage of the fact that MCFAs are more rapidly oxidized for energy than LCFAs. The LCFA provides a source of essential fatty acids.⁶

c) MCFA/LCFA structured lipids are similar to the MCFA/LCFA physical mixture in that they combine the properties of the two types of fatty acids. However, the structured lipid is created through hydrolysis of triglycerides and transesterification of fatty acids to form a composite triglyceride molecule that has various proportions of both MCFA and LCFA. The structured lipids are thought to have an advantage over the physical mixture of MCFA and LCFA because of a slower rate of release and utilization of the MCFA.⁶These products are currently investigational only.

4. Water: Sterile water is added to most PN admixtures to adjust the total volume of fluid needed to meet the prescribed 24-hour fluid intake via PN. This is a convenient and economical way to create a PN admixture when concentrated dextrose, amino acids, and IVFE are used as the base products.

5. Electrolytes: Electrolytes are included in the PN admixture to maintain electrolyte homeostasis. Electrolyte balance is dependent on many factors, such as renal function, acid-base balance, gastrointestinal losses, and medications. Therefore, electrolyte

7

Parenteral Nutrition

Formulations: Preparation and Ordering

Vanessa J. Kumpf, PharmD, BCNSP;

Jay M. Mirtallo, MS, RPh, BCNSP;

Craig Petersen, RD, CNSD

S E C T I O N I Fundamentals of Nutrition Support Practice and Management

intake needs to be individualized in many patients. In stable, uncomplicated patients, a multiple-electrolyte formulation containing standard doses of several electrolytes or several single- entity electrolyte solutions may be used in a PN admixture. The electrolyte composition of PN admixtures is also dependent on the compatibility of each electrolyte with the other components of the PN admixture (see Section II.B).

a) Sodium is available as the chloride, acetate, bicarbonate, phosphorus, or lactate salt. The bicarbonate form should not be used in PN admixtures, as it may cause precipitation of other additives, particularly calcium and magnesium. Lactate is consid- ered an inferior choice relative to acetate, as acetate is more readily metabolized to bicarbonate intravenous (IV) sodium and is dosed in milliequivalent units.

b) Potassium is available as the chloride, acetate, or phosphorus salt. IV potassium is dosed in milliequivalent units.

c) Phosphorus is available as the sodium or potassium salt. IV phosphorus is dosed in millimoles.

d) Magnesium is available as the sulfate or chloride salt. IV magnesium is dosed in milliequivalent units.

e) Calcium is available as the chloride or gluconate salt. Calcium gluconate is the preferred form of calcium for PN admixtures because it is more stable in solution and, therefore, is less likely to dissociate and form a precipitate with phosphorus. IV calcium is dosed in milliequivalent units.

f) The choice of the chloride versus acetate salt of sodium and potassium depends on the patient’s acid-base status. Generally, acid-base balance can be maintained by using approximately equal amounts of chloride and acetate (ie, a 1:1 ratio). Acetate and chloride are also present in the base amino acid solutions in various amounts. If a patient has altered acid-base status, the chloride-acetate ratio may need to be adjusted. For example, if metabolic acidosis is present, maximum acetate and minimum chloride should be used in the PN admixture. Conversely, if metabolic alkalosis is present, maximum chloride and minimum acetate should be used.

6. Vitamins are added to the PN admixture daily, usually as a fixed dose using a multivitamin preparation. Parenteral vitamins have limited stability once they are added to the PN admixture. In gen- eral, they are stable for 24 hours.⁷

a) Adult: Available parenteral multivitamin products for adults contain 12 or 13 known vitamins (with or without vitamin K). In 2000, the US Food and Drug Administration (FDA) amended requirements for marketing an “effective” adult parenteral vitamin formulation and recommended changes to the 12-vitamin formulation that had been available for over 20 years.⁸The new requirements call for increased dosages of vitamins B1(thiamine), B6(pyridoxine), C (ascorbic acid), and folic acid as well as addition of vitamin K. An adult parenteral vitamin formulation meeting the 2000 reformulation requirements but without vitamin K has also received FDA approval and is commercially available.

b) Pediatric: Parenteral multivitamin products are available for pediatric patients who are up to age 11 years or who weigh up to 40 kg. They are formulated to comply with the Subcommit- tee on Pediatric Parenteral Nutrient Requirements of the Com- mittee on Clinical Practice Issues of the American Society for Clinical Nutrition.⁹

c) Individual vitamin products are used to supplement multivitamin doses when a deficiency state exists or when there are increased needs because of a disease or clinical condition.

Single-entity parenteral vitamin products include vitamin B1

(thiamine), vitamin B2(riboflavin), vitamin B6(pyridoxine), vitamin B12(cyanocobalamin), folic acid, vitamin C, vitamin A, and vitamin K. Vitamin D can also be given by intramuscular administration.

7. Trace minerals are essential to normal metabolism and growth.

Although relatively minute amounts of trace minerals are required, deficiency states may develop fairly rapidly when increased metabolic requirements (eg, burn injury), increased losses (eg, large-volume fistula output), or rapid growth are present. The recommended daily requirement (plus supplemen- tal replacement doses as needed for increased requirements or losses) should be included in all PN admixtures. There are, however, clinical conditions necessitating trace mineral restriction (eg, decreased copper and manganese excretion with biliary disease), and therefore the recommended daily requirement may need adjustment. Trace minerals available for parenteral admixture include chromium, copper, iodine, iron, manganese, molybdenum, selenium, and zinc.

a) Standard multiple–trace element solutions are available in several combinations with as few as four (chromium, copper, manganese, zinc) and as many as seven (chromium, copper, iodine, manganese, molybdenum, selenium, zinc) trace elements. The doses of each trace element in the recommended daily volume for admixture usually are based on the American Medical Asso- ciation National Advisory Group recommendations for daily parenteral trace element intake.¹⁰Separate products exist for adult and pediatric patients.

b) Single-entity trace element solutions are available to use when individual trace element requirements cannot be met with the multiple–trace element products. Single-entity products exist for chromium, copper, iodine, iron, manganese, molybdenum, selenium, and zinc. Iron dextran may be added to non-IVFE- containing PN formulations but requires caution due to compatibility limitations.¹¹It should not be added to a total nutrient admixture (TNA) because it can destabilize the IVFE (see Sec- tion II.C.2). Iron sucrose and sodium ferric gluconate provide therapeutic options for the parenteral supplementation of iron, but compatibility data with PN formulations are not available.¹¹ B. Contaminants of PN formulation components: Many components of the PN formulation have been shown to be contaminated with trace elements such as zinc, copper, manganese, chromium, selenium, and aluminum.¹²Manganese and aluminum appear to be the most clini- cally relevant trace element contaminants.

1. Aluminum: Toxicity due to aluminum contamination in PN formulations can cause significant clinical problems.¹³As a result, the FDA developed regulations that require manufacturers to disclose on the label the aluminum content of small- and large- volume parenteral products used in the preparation of PN (as of July 2004).¹⁴

a) The safe limit of aluminum in PN has been set at 5 mcg/kg/

day.¹⁴

b) The intent of the regulation is to educate health care practi- tioners about aluminum exposure and facilitate the preparation of low-aluminum parenteral solutions to patients in high-risk groups.

c) High-risk groups include infants and neonates receiving PN for a period longer than 10 days and any patient receiving long- term PN who has renal compromise.

d) Renal compromise is associated with central nervous system manifestations of aluminum toxicity.

S E C T I O N I Fundamentals of Nutrition Support Practice and Management

e) Infants and neonates are extremely vulnerable to aluminum toxicity, which is manifested by alterations in bone formation and mineralization, encephalopathy, and impaired neurologic development.^13,14These patients are at higher risk because of the excess aluminum burden per kg body weight infused with PN, the infant’s inability to regulate the body’s aluminum content due to immature renal function, and the impact of aluminum on growth and development.

f ) Aluminum contamination of products used in PN preparation comes primarily from raw materials during the manufacturing process and can therefore vary by manufacturer and lot. The aluminum sources of most concern are calcium and phosphate salts.

g) Adults receiving long-term home PN have had problems with osteopenia and bone mineralization, in part caused by aluminum.¹³This problem has been partially improved by the replacement of casein hydrolysates with crystalline amino acid products as the source of protein and reduction in the aluminum in PN formulations.

2. Manganese: Manganese toxicity associated with PN has been reported, most notably in long-term home PN patients.¹⁵Hyper- manganesemia may lead to manganese deposition in the basal ganglia and neurological symptoms. Manganese contamination of PN additives has been identified as a factor contributing to hypermanganesemia. The level of contamination appears to vary by manufacturer and lot number. Manganese concentrations ranging from 8 to 22 mcg per total daily volume have been reported in PN formulations with no added manganese.¹⁶It may, therefore, be necessary to eliminate the use of multiple–trace element products that contain added manganese in long-term home PN patients with hypermanganesemia and instead use single-entity trace element solutions.

C. Types of PN formulations

1. Dextrose/amino acids (2-in-1): Dextrose and amino acids are mixed with electrolytes, vitamins, and trace elements. These formulations are typically mixed in single-liter volumes. However, in some circumstances the components may be in a container that provides a 24-hour supply of nutrients. IVFE are infused separately.

2. TNAs: Under specific circumstances, IVFE can be admixed with the other components of PN to create a TNA.¹⁷All the parenteral nutrient components are mixed in one container that sup- plies the 24-hour nutrient intake. There are both advantages and disadvantages associated with a TNA when compared to a 2-in-1 formulation with a separate IVFE infusion.¹⁸

a) Advantages

(1) Decreased nursing time: Since a TNA system uses only one container per day, nursing time involved in IV setup and administration is decreased.

(2) Decreased risk of touch contamination: Fewer manipula- tions of the catheter and administration set are required, decreasing the risk of touch contamination. This may decrease the risk of catheter-related infection.

(3) Decreased pharmacy preparation time: Compared with admixing multiple single-liter containers of the PN admixture for each patient each day, it takes less time to admix a single 24-hour supply of the PN admixture, especially if an automated compounder is available.

(4) Cost savings: Less nursing and pharmacy time plus fewer materials used in admixing and administering the PN formulation result in lower cost. For example, the infusion pump and administration set for a separate IVFE infusion are not required.

(5) Ease of administration for home PN patients: Using a single container per day rather than piggybacking a separate container of lipid into the PN admixture is simpler for most patients. It eliminates the need for two separate infusion pumps and administration sets. As a result, it can signifi- cantly improve quality of life.

(6) Better fat utilization: A slow, continuous infusion of IVFE has been shown to be better tolerated than a shorter IVFE infusion period, as demonstrated by reticuloendothelial system impairment.^18,19

b) Disadvantages

(1) Diminished stability and compatibility: Addition of IVFE to the PN admixture decreases the overall stability of the fat emulsion. If the fat emulsion separates from the other components after it is prepared and then is infused, there could be potentially life-threatening consequences (see Section III.B). There are limitations to the amounts of nutrients that can be combined when IVFE is present in the PN admixture. This is due to the properties of the fat emulsion and the ease with which it can be disrupted by substances such as divalent and trivalent electrolytes (see Section II.B.).

(2) Impaired visual inspection of the TNA: Addition of IVFE renders the PN admixture opaque. Therefore, visual inspection, one of the most frequently used methods of checking for solution impurities or precipitates, is obscured. This increases the risk of infusing an admixture that may harm the patient.^20–21

D. Order of admixing: The order in which the components of a PN admixture are combined can affect the overall stability of the final product. The additive sequence in compounding must be opti- mized and validated as a safe and efficacious method.²²The order of admixing is determined by the method used (eg, automated vs gravity).

1. Automated compounding: The procedure depends on the specific automated compounding device being used. Assistance in optimizing the compounding order for automated devices should be obtained through consultation with the manufacturer of macronutrients being used as well as the manufacturer of the compounding device because brand-specific issues might influence the compatibility of the final formulation.²²

2. Gravity transfer: The steps below should be followed in the order presented (step afirst and step jlast) to optimize the stability of the PN admixture.²³

a) Combine dextrose, amino acids, and water.

b) Add phosphorus.

c) Add sodium, potassium, and magnesium (in any order).

d) Add trace minerals.

e) Agitate the solution well.

f ) Add calcium (or a calcium-containing multielectrolyte solution) and agitate the solution well again.

g) Observe the solution for precipitates or contaminants (eg, rubber cores). If either is present, discard the solution. If a precipitate is present, review the quantities of additives for incompatibilities (especially calcium and phosphorus; see Sec- tion II.B.1) and adjust nutrient doses as needed to achieve compatibility (see Section II.B.1.e). Review the order of mixing and remix the solution.

h) If a TNA is being admixed, add the IVFE next, gently agitate, and observe for signs of the emulsion cracking (see Section III.B.2).

S E C T I O N I Fundamentals of Nutrition Support Practice and Management

i) Add vitamins last, as close to the time of administration of the PN admixture as possible. For home PN patients, the patient or caregiver should add vitamins just prior to infusion.

j) Note that when a TNA is admixed, dextrose and IVFE should never be added directly to one another. The low pH of dextrose solutions will disrupt the IVFE.

E. Admixture osmolarity refers to the osmoles of solute per liter of solution. Osmolarity is measured in milliosmoles per liter (mOsm/L). PN admixture osmolarity is important because the IV access site used for a given infusion is dictated by admixture osmolarity. The higher the osmolarity, the larger the vein needed to accommodate the formulation. A formulation with high osmolarity infused into a small peripheral vein will cause irritation and pain, with damage to the vessel (phlebitis), which will necessitate frequent changes of the IV site.

1. Central vein infusion guidelines: Due to the high osmolarity of most PN formulations, they are limited to administration through a central venous access catheter with tip placement in the superior vena cava adjacent to the right atrium.^22,24Because of the high rate of blood flow through the central vein, the formulation is rapidly diluted and is not harmful to the vessel. There are no known upper limits to solution osmolarity via the central vein; however, the maximum is usually limited by the concentration of available base solutions used in compounding the PN formulation.

2. Peripheral vein infusion guidelines: Typically, a peripheral vein can tolerate a formulation of up to 600 mOsm/L without any irritation or damage. As the osmolarity of the formulation increases above 600 mOsm/L, the likelihood of vein irritation and damage increases. Data indicate that an appropriate standard maximum osmolar concentration for a peripheral PN admixture is 900 mOsm/L.²⁵

3. Estimating osmolarity: Formulation osmolarity can be estimated by adding the osmolar contribution from each component of the PN formulation and dividing by the total volume (in liters) of the formulation. The approximate osmolar contribution of commonly used components of a PN admixture is as follows²²:

a) Amino acids: 1 g =10 mOsm b) Dextrose: 1 g =5 mOsm

c) 20% IVFE: 1 g =0.71 mOsm (product dependent) d) Calcium gluconate: 1 mEq =1.4 mOsm

e) Magnesium sulfate: 1 mEq =1 mOsm

f ) Potassium (chloride, acetate, or phosphate salt): 1 mEq = 2 mOsm

g) Sodium (chloride, acetate, or phosphate salt): 1 mEq = 2 mOsm

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