AHFS Class:

40:20 Caloric Agents

The compositions and characteristics of lipid emulsion, intravenous, products are listed in Table 1.

Table 1. Composition and Characteristics of Several Lipid Emulsion, Intravenous, Products

^aNot for direct infusion.^bMust be combined with dextrose and amino acid solutions such that the final concentration of fat in the total nutrient admixture (TNA) does not exceed 20%.

In addition, lipid emulsion, intravenous (as Intralipid 20%), is available as one component of 3-chamber bag products that also contain amino acids with electrolytes and dextrose in a fixed volume and concentration (i.e., Kabiven and Perikabiven, both by Fresenius Kabi).³²⁶⁴; ³²⁶⁵ The specific product labeling should be consulted for additional details on the formulation, administration, and stability of these products.³²⁶⁴; ³²⁶⁵

pH

The pH of lipid emulsion, intravenous, products is adjusted with sodium hydroxide to a pH ranging from 6 to 8.9³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴ or 9.³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷

Osmolality

The osmolalities of lipid emulsion, intravenous, products range from 310 to 390 mOsm/kg and are listed in Table 1.

Osmolarity

The osmolarities of lipid emulsion, intravenous, products range from 200 to 290 mOsm/L and are listed in Table 1.

Phosphate Content

The phosphate content of Intralipid 20%, Intralipid 30%, Smoflipid 20%, and Omegaven 10% is 15 mmol/L.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁵; ³⁴⁴⁴

Aluminum Content

Lipid emulsion, intravenous, products contain no more than 25 mcg of aluminum per L.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷

Trade Name(s)

Clinolipid, Intralipid, Nutrilipid, Omegaven, SMOFlipid

Lipid emulsion, intravenous 10 and 20%, may be administered alone by intravenous infusion via a peripheral or central vein through a 1.2-µm inline filter.³²⁵¹; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷ Lipid emulsion, intravenous, also may be administered by intravenous infusion in total nutrient admixtures (TNA, “3-in-1”) in combination with amino acids, dextrose, and other nutrients; however, selection of the peripheral or central venous route depends upon the osmolarity of the final infusate.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴ Some manufacturers state that solutions with an osmolarity of 900 mOsm/L or more must be infused through a central vein.³²⁵⁵; ³⁴⁴⁴

Administration sets and containers must not contain diethylhexyl phthalate (DEHP).³²⁵¹; ³²⁵⁴; ³²⁵⁵; ³²⁵⁶; ³⁴⁴⁴; ⁴⁰²⁷

Lipid emulsion, intravenous, in pharmacy bulk packages is used as a component in parenteral nutrition admixtures; lipid emulsion, intravenous, in pharmacy bulk packages is not intended for direct intravenous administration.³²⁵²; ³²⁵³; ³²⁵⁴; ⁴⁰²⁷

The product labeling for Intralipid 20%, Nutrilipid 20%, Smoflipid 20%, and Omegaven 10% states that the product may be infused concurrently into the same vein as dextrose-amino acid solutions by a Y-connector located near the infusion site.³²⁵¹; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴ The manufacturer states the infusion should be started immediately after connecting the infusion set and completed within 12 hours when using a Y-connector or within 24 hours when used as part of an admixture³²⁵¹; ³²⁵⁵; ³⁴⁴⁴

The American Society of Parenteral and Enteral Nutrition (ASPEN) also recommends changing administration tubing and filters for lipid emulsion, intravenous, every 12 hours when administered as a separate infusion, or 24 hours when administered as a component of a total nutrient admixture (TNA) to reduce the risk of antimicrobial contamination and/or infection.³²⁵⁶

The specific product labeling should be consulted for additional details on initial infusion rates, titration, and maximum infusion rates in various populations.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷

Lipid emulsion, intravenous, products should be stored in the intact containers at controlled room temperature³²⁵⁴; ⁴⁰²⁷ or at temperatures below 25°C and avoiding excessive heat; the specific manufacturer’s instructions should be consulted.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁵; ³⁴⁴⁴ Protect from freezing; any product that has been frozen should be discarded.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷ Products in flexible containers are packaged in an overwrap with an oxygen exposure indicator which should be inspected before opening the overwrap.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ⁴⁰²⁷ Do not use the product if the oxygen exposure indicator does not meet specifications.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ⁴⁰²⁷ Store intact bags in overwrap until ready for use.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ⁴⁰²⁷

After removal from overwrap, if not used immediately, Intralipid 20%, Intralipid 30%, and Smoflipid 20% may be stored at 2 to 8°C for up to 24 hours.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁵ Clinolipid 20%, if not used immediately after removal from overwrap, may be stored at temperature not exceeding 25°C for up to 24 hours;⁴⁰²⁷ however, the manufacturer states the product is stable out of the overwrap for 7 days refrigerated (2 to 8°C) protected from light, or 3 days at room temperature (20 to 25°C) protected from light.⁴⁰⁴³

The specific product labeling should be consulted for additional details on stability of admixtures. In general, admixtures containing lipid emulsion, intravenous, should be used immediately after preparation, but may be stored for up to 24 hours under refrigeration at 2 to 8°C.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴ Admixtures containing Omegaven may alternatively be stored for up to 6 hours at room temperature.³⁴⁴⁴ Infusion of admixtures should be completed within 24 hours after removal from such storage at 2 to 8°C.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴ The manufacturer of Clinolipid 20% states admixtures containing Clinolipid are stable for 9 days refrigerated (2 to 8°C) plus an additional 48 hours at room temperature (23 to 27°C).⁴⁰⁴⁴

Admixtures containing lipid emulsion, intravenous, should be protected from light.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷

If using pharmacy bulk packages, the contents of the pharmacy bulk packages should be used within 4 hours once the closure is penetrated.³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ⁴⁰²⁷

Excessive acidity (e.g., pH less than 5) and inappropriate electrolyte content are the primary destabilizers of emulsions.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴ A 2-year study of Intralipid 10% found an increase in free fatty acids and a decrease in pH on storage. Gross particles formed and toxicity to rabbits increased with time. These changes were greatest during storage at 40°C but were measurable at 20 and even 4°C. The toxicity of the emulsions to rabbits could be correlated to the extent of free fatty acid formation in the emulsions. The formation of free fatty acids, with a consequent lowering of pH, is the major route of degradation of lipid emulsions. The rate of degradation is minimized at pH 6 to 7.⁸⁸⁹

The container-closure system is important for long-term stability. Plastic containers are generally permeable to oxygen, which can readily oxidize the lipid emulsions, so glass bottles have been used. Furthermore, the stoppers must not be permeable to oxygen and must not soften on contact with the emulsions. Teflon-coated stoppers have been recommended. Finally, the emulsions are packed under an atmosphere of nitrogen.⁸⁸⁹; ³⁴²⁰; ³⁴²¹; ³⁴²²

The long-term room temperature stability of the emulsions is lost when the intact containers are entered. The integrity of the nitrogen layer in the sealed container is essential for room temperature stability. Exposure of Intralipid 10% to the atmosphere has resulted in gradual changes in the emulsion system. No changes in the particle size distribution occurred during the first 36 hours of room temperature storage. After 48 hours at room temperature, globule coalescence was noticeable. By 72 hours, the changes had become significant; however, the visual appearance after 72 hours was unchanged. Long-term storage for 15 months at room temperature resulted in formation of a nonhomogeneous cream layer with oil globules on top.⁶⁵⁶; ⁶⁵⁷ If the pH of the emulsion is optimal and the emulsion is stored under nitrogen and not exposed to direct sunlight, oxidative degradation is not likely to be significant.⁸⁸⁹

The lipid emulsion should be a homogenous emulsion with a milky white appearance.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷ Do not use if discoloration or particulate matter is present, or separation of the emulsion is evident.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷

Unused portions should be discarded.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷

Lipid emulsion, intravenous, has been shown to support the growth of various microbes, including both bacterial and fungal species. No visual changes occurred in the emulsions to suggest contamination.¹¹⁰²; ¹¹⁰³; ¹¹⁰⁴; ¹²¹⁶ The potential for microbiological growth should be considered when assigning expiration periods.

The 3-in-1 parenteral nutrition solutions that have a lower pH and higher osmolality due to the presence of amino acids and dextrose reportedly do not support microbial growth as well as lipid emulsion alone;¹²¹⁶ however, this risk still exists and the use of strict aseptic technique in the preparation of such admixtures is essential.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷

See Additional Compatibility Information for other information on stability of lipid emulsion, intravenous, including stability of multicomponent (3-in-1) admixtures.

Freezing Emulsions

Freezing may cause physical damage. The emulsions may become coarse and coalesce, and they can undergo irreversible phase separation.⁵⁵⁹

The emulsions should not be frozen.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷ If accidental freezing occurs, the products should be discarded.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴

Syringes

The physical stability of lipid emulsion, intravenous (ClinOleic 20%, Baxter; Intralipid 20%, Fresenius Kabi; Lipofundin MCT/LCT, Braun; Omegaven 10%, Fresenius Kabi; Smoflipid, Fresenius Kabi), packaged as 20 mL in 20-mL polypropylene syringe (Becton Dickinson) was evaluated at 4°C, 25°C with 60% relative humidity, and 40°C with 75% relatively humidity.³⁴⁵⁷; ³⁴⁵⁸ Visual and microscopic observations, pH analysis, measurement of oil droplet size (via laser diffraction and photon correlation spectroscopy methods), and zeta potential analysis were performed.³⁴⁵⁷ The author concluded that the emulsions were physically stable for 30 days at 4 and 25°C and for 21 days at 40°C.³⁴⁵⁷

Plasticizer Leaching

Diethylhexyl phthalate (DEHP)-containing devices (e.g., containers, administration sets, lines), including those that contain PVC should not be used for the administration of lipid emulsion, intravenous.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³²⁵⁹; ³⁴⁴⁴; ⁴⁰²⁷ The amount of plasticizer leached from PVC sets by lipid emulsion is directly related to the length of administration time and inversely related to the flow rate; these two factors influence the amount of contact time between the lipid emulsion and the PVC tubing. Longer administration times and slower administration rates increase the amount of leached plasticizer. Non-PVC plastic containers, such as an ethylene vinyl acetate (EVA) bag, may be used to avoid plasticizer exposure.⁶⁵⁸; ⁶⁶¹; ⁶⁷³; ⁸⁹³; ¹¹⁰⁵

Storage of Intralipid 10 and 20% for 24 hours in PVC sets resulted in phthalate contents of 64 to 70 mcg/mL at 5°C and 144 to 160 mcg/mL at ambient temperature. When the lipid emulsions were simply infused through PVC sets, phthalate content dropped to 3.6 to 8.5 mcg/mL. A patient being administered 500 mL of lipid emulsion per day would receive about 1.5 to 2.75 mg of phthalate per day. Negligible levels of phthalate were delivered from a parenteral nutrition admixture containing lipid emulsion.¹²⁶⁴

A parenteral nutrition solution containing an amino acid solution, dextrose, and electrolytes in a PVC bag did not leach measurable quantities of DEHP plasticizer during 21 days of storage at 4 and 25°C. However, addition of lipid emulsion 10 or 20% to the formula caused detectable leaching of DEHP from the PVC containers stored for 48 hours. Higher DEHP levels were found in the 25°C samples than in the 4°C samples. The authors recommended limiting the use of lipid-containing parenteral nutrition admixtures to 24 to 36 hours. Use of non-PVC containers and tubing is another option.¹⁴³⁰

Total nutrient admixtures with lipid emulsion concentrations ranging from 1 to 3.85% were found to leach DEHP plasticizer even though they were packaged in EVA bags. The bags had PVC sites in their composition, which contributed the DEHP. Use of PVC administration sets added additional DEHP. Leached DEHP ranged from about 200 mcg to 2 mg during simulated infusions conducted immediately after preparation. The authors concluded that children who are treated regularly with TNA are exposed to significant amounts of DEHP.²⁵⁸⁸

Filtration

A 1.2-µm inline filter should be used in the administration of lipid emulsion, intravenous, when used alone and when administered as a component of a 3-in-1 admixture (TNA), to reduce the potential for patient harm due to particulates, microprecipitates, and air emboli.³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³²⁵⁶; ³²⁵⁹; ³²⁶⁰; ³⁴⁴⁴; ⁴⁰²⁷

Only a 1.2-µm filter should be used; filters with a pore size smaller than 1.2-µm must not be used with lipid emulsions.³²⁵¹; ³²⁵²; ³²⁵³; ⁴⁰²⁷ The particle size of the lipid emulsion products may exceed the porosity of some inline filters, and such small porosity filters should not be used with lipid emulsion products.⁶⁵⁸; ¹¹⁰⁶

Solution Compatibility

Additive Compatibility

Y-Site Injection Compatibility (1:1 Mixture)

Additional Compatibility Information

Calcium and Phosphate

UNRECOGNIZED CALCIUM PHOSPHATE PRECIPITATION IN A 3-IN-1 PARENTERAL NUTRITION MIXTURE RESULTED IN PATIENT DEATH.

The potential for the formation of a calcium phosphate precipitate in parenteral nutrition solutions is well studied and documented,¹⁷⁷¹; ¹⁷⁷⁷ but the information is complex and difficult to apply to the clinical situation.¹⁷⁷⁰; ¹⁷⁷²; ¹⁷⁷⁷ The incorporation of lipid emulsion in 3-in-1 parenteral nutrition solutions obscures any precipitate that is present, which has led to substantial debate on the dangers associated with 3-in-1 parenteral nutrition mixtures and when or if the danger to the patient is warranted therapeutically.¹⁷⁷⁰; ¹⁷⁷¹; ¹⁷⁷²; ²⁰³¹; ²⁰³²; ²⁰³³; ²⁰³⁴; ²⁰³⁵; ²⁰³⁶ Because such precipitation may be life-threatening to patients,²⁰³⁷; ²²⁹¹ FDA issued a Safety Alert containing the following recommendations:¹⁷⁶⁹

1. “The amounts of phosphorus and of calcium added to the admixture are critical. The solubility of the added calcium should be calculated from the volume at the time the calcium is added. It should not be based upon the final volume.
   Some amino acid injections for TPN admixtures contain phosphate ions (as a phosphoric acid buffer). These phosphate ions and the volume at the time the phosphate is added should be considered when calculating the concentration of phosphate additives. Also, when adding calcium and phosphate to an admixture, the phosphate should be added first.
   The line should be flushed between the addition of any potentially incompatible components.
2. A lipid emulsion in a 3-in-1 admixture obscures the presence of a precipitate. Therefore, if a lipid emulsion is needed, either (1) use a 2-in-1 admixture with the lipid infused separately, or (2) if a 3-in-1 admixture is medically necessary, then add the calcium before the lipid emulsion and according to the recommendations in number 1 above.
   If the amount of calcium or phosphate which must be added is likely to cause a precipitate, some or all of the calcium should be administered separately. Such separate infusions must be properly diluted and slowly infused to avoid serious adverse events related to the calcium.
3. When using an automated compounding device, the above steps should be considered when programming the device. In addition, automated compounders should be maintained and operated according to the manufacturer’s recommendations.
   Any printout should be checked against the programmed admixture and weight of components.
4. During the mixing process, pharmacists who mix parenteral nutrition admixtures should periodically agitate the admixture and check for precipitates. Medical or home care personnel who start and monitor these infusions should carefully inspect for the presence of precipitates both before and during infusion. Patients and care givers should be trained to visually inspect for signs of precipitation. They also should be advised to stop the infusion and seek medical assistance if precipitates are noted.
5. A filter should be used when infusing either central or peripheral parenteral nutrition admixtures. At this time, data have not been submitted to document which size filter is most effective in trapping precipitates.
   Standards of practice vary, but the following is suggested: a 1.2-µm air-eliminating filter for lipid-containing admixtures and a 0.22-µm air-eliminating filter for non-lipid-containing admixtures.
6. Parenteral nutrition admixtures should be administered within the following time frames: if stored at room temperature, the infusion should be started within 24 hours after mixing; if stored at refrigerated temperatures, the infusion should be started within 24 hours of rewarming. Because warming parenteral nutrition admixtures may contribute to the formation of precipitates, once administration begins, care should be taken to avoid excessive warming of the admixture.
   Persons administering home care parenteral nutrition admixtures may need to deviate from these time frames. Pharmacists who initially prepare these admixtures should check a reserve sample for precipitates over the duration and under the conditions of storage.
7. If symptoms of acute respiratory distress, pulmonary emboli, or interstitial pneumonitis develop, the infusion should be stopped immediately and thoroughly checked for precipitates. Appropriate medical interventions should be instituted. Home care personnel and patients should immediately seek medical assistance.”

Calcium Phosphate Precipitation Fatalities

Fatal cases of paroxysmal respiratory failure in 2 previously healthy women receiving peripheral vein parenteral nutrition were reported. The patients experienced sudden cardiopulmonary arrest consistent with pulmonary emboli. The authors used in vitro simulations and an animal model to conclude that unrecognized calcium phosphate precipitation in a 3-in-1 TNA caused the fatalities. The precipitation resulted during compounding by introducing calcium and phosphate near to one another in the compounding sequence and prior to complete fluid addition. This resulted in a temporarily high concentration of the drugs and precipitation of calcium phosphate. Observation of the precipitate was obscured by the incorporation of 20% lipid emulsion, intravenous, into the nutrition mixture. No filter was used during infusion of the fatal nutrition admixtures.²⁰³⁷

In a follow-up retrospective review, 5 patients were identified who had respiratory distress associated with the infusion of the 3-in-1 admixtures at around the same time. Four of these 5 patients died, although the cause of death could be definitively determined for only 2.²²⁹¹

Calcium and Phosphate Conditional Compatibility

Calcium salts are conditionally compatible with phosphates in parenteral nutrition mixtures. The incompatibility is dependent on a solubility and concentration phenomenon and is not entirely predictable. Precipitation may occur during compounding or at some time after compounding is completed.

NOTE: Some amino acid solutions inherently contain calcium and phosphate, which must be considered in any projection of compatibility.

Dextrose

Dextrose in final concentrations of 5 to 12.5% has been shown to cause a progressive coalescence of the globules in Intralipid 10% due to its alteration of pH from about 7 down to about 3.5 in 48 hours.⁶⁵⁶

Monovalent Cations

Monovalent cations such as potassium and sodium also cause progressive globule coalescence in Intralipid 10 and 20%, leading to surface creaming.⁴⁸⁰; ⁴⁹⁰; ⁶⁵⁶; ⁸⁹⁰ The degree and rate of this effect are dependent on the concentration of the ions. A decreasing degree and rate of coalescence were noted as concentrations of sodium chloride or potassium chloride decreased. At 200 mEq/L, the rate is rapid and the effect is severe. In the range of 100 mEq/L or less, significant effects may not occur for over 24 hours.⁴⁹⁰; ⁶⁵⁶

Divalent Cations

Divalent cations such as calcium and magnesium cause immediate flocculation, with a nonhomogeneous white granular layer forming at the surface of the Intralipid 10%. This is followed by a substantial, visibly distinct layer, which does not redisperse on shaking.⁴⁸⁰; ⁴⁹⁰; ⁶⁵⁶

The creaming of Intralipid 20% when calcium chloride was admixed in concentrations from 0.25 to 5% was found to be concentration dependent, with maximum creaming occurring with the 5% additive in 30 minutes.⁸⁹⁰

Multicomponent (3-in-1) Admixtures

Because of the potential benefits in terms of simplicity, efficiency, time, and cost savings, the concept of mixing amino acids, carbohydrates, electrolytes, lipid emulsion, and other nutritional components together in the same container has been explored. Within limits, the feasibility of preparing such 3-in-1 parenteral nutrition admixtures has been demonstrated as long as a careful examination of the emulsion mixtures for signs of instability is performed prior to administration.¹⁸¹³

However, these 3-in-1 mixtures are very complex and inherently unstable. Emulsion stability is dependent on both zeta potential and van der Waals forces, influenced by the presence of dextrose.²⁰²⁹ Because the ultimate stability of each mixture is the result of various complicated factors, a definitive prediction of stability is impossible. Death and injury have resulted from administration of unrecognized precipitates in 3-in-1 parenteral nutrition admixtures. In addition, the use of 3-in-1 admixtures is associated with a higher rate of catheter occlusion and reduced catheter life compared with giving the lipid emulsion separately from the parenteral nutrition solution.⁷⁰⁵; ¹⁵¹⁸; ²¹⁹⁴

Intravenous administration of unstable lipid emulsion with a large amount of large fat globules greater than 5 µm is potentially embolic and has been demonstrated to result in liver toxicity.²⁶⁹⁰

The use of a 5-µm inline filter for a 3-in-1 admixture (containing Travasol 8.5%, dextrose, Intralipid 10%, various electrolytes, vitamins, and trace elements) showed that fat, in the form of large globules or aggregates, comprised 99.4% of the filter contents. These authors recommended the use of an appropriate filter for preventing catheter occlusion with 3-in-1 admixtures.⁷⁴²

The presence of glass particles, talc, and plastic has been observed in administration line samples drawn from 20 adults receiving 3-in-1 parenteral nutrition admixtures and in 20 children receiving 2-in-1 admixtures with separate lipid emulsion infusions. Particles ranged from 3 to 5 µm to greater than 40 µm and were more consistently seen in the pediatric admixtures. The authors suggested the use of inline filters given that particulate contamination is present, has no therapeutic value, and can be harmful.²⁴⁵⁸

Combining an amino acids-dextrose parenteral nutrition solution containing various electrolytes with lipid emulsion 20%, intravenous (Intralipid, Vitrum), resulted in a mixture that was apparently stable for a limited time. However, it ultimately exhibited a creaming phenomenon. Within 12 hours, a distinct 2-cm layer separated on the upper surface. Aggregates believed to be clumps of fat droplets were found. Fewer and smaller aggregates were noted in the lower layer.⁵⁶⁰; ⁵⁶¹

Amino acids have been reported to have no adverse effect on the emulsion stability of Intralipid 10%. In addition, the amino acids appeared to prevent the adverse impact of dextrose and to slow the coalescence and flocculation resulting from mono- and divalent cations. However, significant coalescence did result after a somewhat longer time. Therefore, it was recommended that such cations not be mixed with lipid emulsion, intravenous.⁶⁵⁶

Three-in-one TNA admixtures prepared with Intralipid 20% and containing mono- and divalent ions as well as heparin sodium 5 units/mL were found to undergo changes consistent with instability, including fat particle shape and diameter changes as well as creaming and layering. The changes were evident within 48 hours at room temperature but were delayed to between 1 and 2 months when refrigerated.⁵⁸

Travenol stated that 1:1:1 mixtures of amino acids 5.5, 8.5, or 10% (Travenol), lipid emulsion 10 or 20% (Travenol), and dextrose 10 to 70% are physically stable but recommended administration within 24 hours. M.V.I.-12 3.3 mL/L and electrolytes may also be added to the admixtures up to the maximum amounts listed below:⁸⁵⁰

The stability of mixtures of Intralipid 20% 1 L, Vamin glucose (amino acids with dextrose 10%) 1.5 L, and dextrose 10% 0.5 L with various electrolytes and vitamins was evaluated. Initial emulsion particle size was around 1 µm. The mixture containing only monovalent cations was stable for at least 9 days at 4°C, with little change in particle size. The mixtures containing the divalent cations, such as calcium and magnesium, demonstrated much greater particle size increases, with mean diameters of around 3.3 to 3.5 µm after 9 days at 4°C. After 48 hours of storage, however, these increases were more modest, around 1.5 to 1.85 µm. After storage at 4°C for 48 hours followed by 24 hours at room temperature, very few particles exceeded 5 µm. It was found that the effect of particle aggregation caused by electrolytes demonstrates a critical concentration before the effect begins. For calcium and magnesium chlorides, the critical concentrations were 2.4 and 2.6 mmol/L, respectively. Sodium and potassium chloride had critical concentrations of 110 and 150 mmol/L, respectively. The rate of particle aggregation increased linearly with increasing electrolyte concentration. Heparin 667 units/L had no effect on emulsion stability. The quantity of emulsion in the mixture had a relatively small influence on stability, but higher concentrations exhibited a somewhat greater coalescence.⁸⁹²

Instability of the emulsion systems is manifested by (1) flocculation of oil droplets to form aggregates that produce a cream-like layer on top or (2) coalescence of oil droplets leading to an increase in the average droplet size and eventually to a separation of free oil. The lowering of pH and addition of electrolytes can adversely affect the mechanical and electrical properties at the oil-water interface, eventually leading to flocculation and coalescence. Amino acids act as buffering agents and provide a protective effect on emulsion stability. Addition of electrolytes, especially the divalent ions Mg⁺⁺ and Ca⁺⁺ in excess of 2.5 mmol/L, to simple lipid emulsions causes flocculation. But in mixed parenteral nutrition solutions, the stability of the emulsion is enhanced, depending on the quantity and nature of the amino acids present. The authors recommended a careful examination of emulsion mixtures for instability prior to administration.⁸⁴⁹

The stability of an amino acid 4% (Travenol), dextrose 14%, and lipid emulsion 4% (Pharmacia) parenteral nutrition solution was reported to be quite good. The solution also contained electrolytes, vitamins, and heparin sodium 4000 units/L. The aqueous solution was prepared first, with the lipid emulsion added subsequently. This procedure allowed visual inspection of the aqueous phase and reduced the risk of emulsion breakdown by the divalent cations. Sample mixtures were stored at 18 to 25 and 3 to 8°C for up to 5 days. They were evaluated visually and with a Coulter counter for particle size measurements. Both room temperature and refrigerated mixtures were stable for 48 hours. A marked increase in particle size was noted in the room temperature sample after 72 hours, but refrigeration delayed the changes. The authors’ experience with over 1400 mixtures for administration to patients resulted in one emulsion creaming and another cracking. The authors had no explanation for the failure of these particular emulsions.⁸⁴⁸

Six parenteral nutrition solutions having various concentrations of amino acids, dextrose, soybean oil emulsion (Kabi-Vitrum), electrolytes, and multivitamins were reported. All of the admixtures were stable for 1 week under refrigeration followed by 24 hours at room temperature, with no visible changes, pH changes, or significant particle size changes.¹⁰¹³ However, other researchers questioned this interpretation of the results.¹⁰¹⁴; ¹⁰¹⁵

The stability of 3-in-1 parenteral nutrition solutions prepared with 500 mL of Intralipid 20%, compared to Soyacal 20%, along with 500 or 1000 mL of FreAmine III 8.5% and 500 mL of dextrose 70% was reported. Also present were relatively large amounts of electrolytes and other additives. All mixtures were similarly stable for 28 days at 4°C followed by 5 days at 21 to 25°C, with little change in the emulsion. A slight white cream layer appeared after 5 days at 4°C, but it was easily dispersed with gentle agitation. The appearance of this cream layer did not statistically affect particle size distribution. The authors concluded that the emulsion mixture remained suitable for clinical use throughout the study period. The stability of other components was not evaluated.¹⁰¹⁹

The stability of 3-in-1 parenteral nutrition admixtures prepared with Liposyn II 10 and 20%, Aminosyn pH 6, and dextrose along with electrolytes, trace metals, and vitamins was reported. Thirty-one different combinations were evaluated. Samples were stored under the following conditions: (1) 25°C for 1 day, (2) 5°C for 2 days followed by 30°C for 1 day, or (3) 5°C for 9 days followed by 25°C for 1 day. In all cases, there was no visual evidence of creaming, free oil droplets, and other signs of emulsion instability. Furthermore, little or no change in the particle size or zeta potential (electrostatic surface charge of lipid particles) was found, indicating emulsion stability. The dextrose and amino acids remained stable over the 10-day storage period. The greatest change of an amino acid occurred with tryptophan, which lost 6% in 10 days. Vitamin stability was not tested.¹⁰²⁵

The stability of 4 parenteral nutrition admixtures, ranging from 1 L each of amino acids 5.5% (Travenol), dextrose 10%, and lipid emulsion 10% (Travenol) up to a “worst case” of 1 L each of amino acids 10% with electrolytes (Travenol), dextrose 70%, and lipid emulsion 10% (Travenol) was reported. The admixtures were stored for 48 hours at 5 to 9°C followed by 24 hours at room temperature. There were no visible signs of creaming, flocculation, or free oil. The mean emulsion particle size remained within acceptable limits for all admixtures, and there were no significant changes in glucose, soybean oil, and amino acid concentrations. The authors noted that 2 factors were predominant in determining the stability of such admixtures: electrolyte concentrations and pH.¹⁰⁶⁵

Several parenteral nutrition solutions containing amino acids (Travenol), glucose, and lipid, with and without electrolytes and trace elements, produced no visible flocculation or any significant change in mean emulsion particle size during 24 hours at room temperature.¹⁰⁶⁶

The compatibility of 10 parenteral nutrition admixtures, evaluated over 96 hours while stored at 20 to 25°C in both glass bottles and EVA bags, was reported. A slight creaming occurred in all admixtures, but this cream layer was easily dispersed by gentle shaking. No fat globules were visually apparent. The mean drop size was larger in the cream layer, but no globules were larger than 5 µm. Analyses of the concentrations of amino acids, dextrose, and electrolytes showed no changes over the study period. The authors concluded that such parenteral nutrition admixtures can be prepared safely as long as the component concentrations are within the following ranges:¹⁰⁶⁷

The stability of 8 parenteral nutrition admixtures with various ratios of amino acids, carbohydrates, and fat, consisting of FreAmine III 8.5%, dextrose 70%, and Soyacal 10 and 20% (mixed in ratios of 2:1:1, 1:1:1, 1:1:½, and 1:1:¼, where 1 = 500 mL), was evaluated. Additive concentrations were high to stress the admixtures and represent maximum doses likely to be encountered clinically:

The admixtures were stored at 4°C for 14 days followed by 4 days at 22 to 25°C. After 24 hours, all admixtures developed a thin white cream layer, which was readily dispersed by gentle agitation. No free oil droplets were observed. The mean particle diameter remained near the original size of the Soyacal throughout the study. Few particles were larger than 3 µm. Osmolality and pH also remained relatively unchanged.¹⁰⁶⁸

Parenteral nutrition 3-in-1 admixtures with Aminosyn and Liposyn have been a problem. Standard admixtures were prepared using Aminosyn 7% 1000 mL, dextrose 50% 1000 mL, and Liposyn 10% 500 mL. Concentrated admixtures were prepared using Aminosyn 10% 500 mL, dextrose 70% 500 mL, and Liposyn 20% 500 mL. Vitamins and trace elements were added to the admixtures along with the following electrolytes:

Samples of each admixture were (1) stored at 4°C, (2) adjusted to pH 6.6 with sodium bicarbonate and stored at 4°C, or (3) adjusted to pH 6.6 and stored at room temperature. Compatibility was evaluated for 3 weeks.

Signs of emulsion deterioration were visible by 96 hours in the standard admixture and by 48 hours in the concentrated admixture. Clear rings formed at the meniscus, becoming thicker, yellow, and oily over time. Free-floating oil was obvious in 3 weeks in the standard admixture and in 1 week in the concentrated admixture. The samples adjusted to pH 6.6 developed visible deterioration later than the others. The authors indicated that pH may play a greater role than temperature in emulsion stability. However, precipitation (probably calcium phosphate and possibly carbonate) occurred in 36 hours in the pH 6.6 concentrated admixture but not the unadjusted (pH 5.5) samples. Mean particle counts increased for all samples over time but were greatest in the concentrated admixtures. The concentrated admixtures were unsatisfactory for clinical use because of the early increase in particles and precipitation. Furthermore, the standard admixtures should be prepared immediately prior to use.¹⁰⁶⁹

The physical stability of 10 parenteral nutrition admixtures with different amino acid sources was studied. The admixtures contained 500 mL each of dextrose 70%, lipid emulsion 20% (Alpha Therapeutics), and amino acids in various concentrations from each manufacturer. Also present were standard electrolytes, trace elements, and vitamins. The admixtures were stored for 14 days at 4°C, followed by 4 days at 22 to 25°C. Slight creaming was evident in all admixtures but redispersed easily with agitation. Emulsion particles were uniform in size, showing no tendency to aggregate. No cracked emulsions occurred.¹²¹⁷

The stability of parenteral nutrition solutions containing amino acids, dextrose, and lipid emulsion along with electrolytes, trace elements, and vitamins has been described. In one study the admixtures were stable for 24 hours at room temperature and for 8 days at 4°C. The visual appearance and particle size of the lipid emulsion showed little change over the observation periods.¹²¹⁸ In another study variable stability periods were found, depending on electrolyte concentrations. Stability ranged from 4 to 25 days at room temperature.¹²¹⁹

The effects of dilution, dextrose concentration, amino acids, and electrolytes on the physical stability of 3-in-1 parenteral nutrition admixtures prepared with Intralipid 10% or Travamulsion 10% was studied. Travamulsion was affected by dilution up to 1:14, exhibiting an increase in mean particle size, while Intralipid remained virtually unchanged for 24 hours at 25°C and for 72 hours at 4°C. At dextrose concentrations above 15%, fat droplets larger than 5 µm formed during storage for 24 hours at either 4°C or room temperature. The presence of amino acids increased the stability of the lipid emulsions in the presence of dextrose. Fat droplets larger than 5 µm formed at a total electrolyte concentration above approximately 240 mmol/L (monovalent cation equivalent) for Travamulsion 10% and 156 mmol/L for Intralipid 10% in 24 hours at room temperature, although creaming or breaking of the emulsion was not observed visually.¹²²¹

The stability of 43 parenteral nutrition admixtures composed of various ratios of amino acid products, dextrose 10 to 70%, and 4 lipid emulsions 10 and 20% with electrolytes, trace elements, and vitamins was studied. One group of admixtures included Travasol 5.5, 8.5, and 10%, FreAmine III 8.5 and 10%, Novamine 8.5 and 11.4%, Nephramine 5.4%, and RenAmine 6.5% with Liposyn II 10 and 20%. In another group, Aminosyn II 7, 8.5, and 10% was combined with Intralipid, Travamulsion, and Soyacal 10 and 20%. A third group consisted of Aminosyn II 7, 8.5, and 10% with electrolytes combined with the latter 3 lipid emulsions. The admixtures were stored for 24 hours at 25°C and for 9 days at 5°C followed by 24 hours at 25°C. A few admixtures containing FreAmine III and Novamine with Liposyn II developed faint yellow streaks after 10 days of storage. The streaks readily dispersed with gentle shaking, as did the creaming present in most admixtures. Other properties such as pH, zeta potential, and osmolality underwent little change in all of the admixtures. Particle size increased fourfold in one admixture (Novamine 8.5%, dextrose 50%, and Liposyn II in a 1:1:1 ratio), which the authors noted signaled the onset of particle coalescence. Nevertheless, the authors concluded that all of the admixtures were stable for the storage conditions and time periods tested.¹²²²

The stability of 24 parenteral nutrition admixtures composed of various ratios of Aminosyn II 7, 8.5, or 10%, dextrose, and Liposyn II 10 and 20% with electrolytes, trace elements, and vitamins was studied. Four admixtures were stored for 24 hours at 25°C, 6 admixtures were stored for 2 days at 5°C followed by 1 day at 30°C, and 14 admixtures were stored for 9 days at 5°C followed by 1 day at 25°C. No visible instability was evident. Creaming was present in most admixtures but disappeared with gentle shaking. Other properties such as pH, zeta potential, particle size, and concentrations of the amino acids and dextrose showed little or no change during storage.¹²²³

The emulsion stability of 5 parenteral nutrition formulas (TNA #126 through #130 in Appendix) containing Liposyn II in concentrations ranging from 1.2 to 7.1% were reported. The parenteral nutrition solutions were prepared using simultaneous pumping of the components into empty containers (as with the Nutrimix compounder) and sequential pumping of the components (as with Automix compounders). The solutions were stored for 2 days at 5°C followed by 24 hours at 25°C. Similar results were obtained for both methods of preparation using visual assessment and oil globule size distribution.¹⁴²⁶

The stability of 24 parenteral nutrition admixtures containing various concentrations of Aminosyn II, dextrose, and Liposyn II with a variety of electrolytes, trace elements, and multivitamins in dual-chamber, flexible, Nutrimix containers was studied as well. No instability was visible in the admixtures stored at 25°C for 24 hours or in those stored for 9 days at 5°C followed by 24 hours at 25°C. Creaming was observed, but neither particle coalescence nor free oil was noted. The pH, particle size distribution, and amino acid and dextrose concentrations remained acceptable during the observation period.¹⁴³²

The physical stability of 10 parenteral nutrition formulas (TNA #149 through #158 in Appendix) containing TrophAmine and Intralipid 20%, Liposyn II 20%, and Nutrilipid 20% in varying concentrations with low and high electrolyte concentrations was studied. All test formulas were prepared with an automatic compounder and protected from light. TNA #149 through #156 were stored for 48 hours at 4°C followed by 24 hours at 21°C; TNA #157 and #158 were stored for 24 hours at 4°C followed by 24 hours at 21°C. Although some minor creaming occurred in all formulas, it was completely reversible with agitation. No other changes were visible, and particle size analysis indicated little variation during the study period. The addition of cysteine hydrochloride 1 g/25 g of amino acids, alone or with L-carnitine 16 mg/g fat, to TNA #157 and #158 did not adversely affect the physical stability of 3-in-1 admixtures within the study period.¹⁶²⁰

The physical stability of five 3-in-1 parenteral nutrition admixtures (TNA #167 through #171 in Appendix) was evaluated by visual observation, pH and osmolality determinations, and particle size distribution analysis. All 5 admixtures were physically stable for 90 days at 4°C. However, some irreversible flocculation occurred in all combinations after 180 days.¹⁶⁵¹

The stability of several parenteral nutrition formulas (TNA #159 through #166 in Appendix) with and without iron dextran 2 mg/L was studied. All formulas were physically compatible both visually and microscopically for 48 hours at 4 and 25°C, and particle size distribution remained unchanged. The order of mixing and deliberate agitation had no effect on physical compatibility.¹⁶⁴⁸

The maximum allowable concentrations of calcium and phosphate in a 3-in-1 parenteral nutrition mixture for children (TNA #192 in Appendix) were reported. Added calcium varied from 1.5 to 150 mmol/L, while added phosphate varied from 21 to 300 mmol/L. The mixtures were stable for 48 hours at 22 and 37°C as long as the pH was not greater than 5.7, the calcium concentration was below 16 mmol/L, the phosphate concentration was below 52 mM/L, and the product of the calcium and phosphate concentrations was below 250 mmol²/L².¹⁷⁷³

The influence of 6 factors on the stability of lipid emulsion in 45 different 3-in-1 parenteral nutrition mixtures was evaluated. The factors were amino acid concentration (2.5 to 7%); dextrose (5 to 20%); lipid emulsion, intravenous (2 to 5%); monovalent cations (0 to 150 mEq/L); divalent cations (4 to 20 mEq/L); and trivalent cations from iron dextran (0 to 10 mg elemental iron/L). Although many formulations were unstable, visual examination could identify instability in only 65% of the samples. Electronic evaluation of particle size identified the remaining unstable mixtures. Furthermore, only the concentration of trivalent ferric ions significantly and consistently affected the emulsion stability during the 30-hour test period. Of the parenteral nutrition mixtures containing iron dextran, 16% were unstable, exhibiting emulsion cracking. The authors suggested that iron dextran should not be incorporated into 3-in-1 mixtures.¹⁸¹⁴

The compatibility of 8 parenteral nutrition admixtures, 4 with and 4 without electrolytes, comparing Liposyn II and Intralipid (TNA #250 through #257 in Appendix) was reported. The 3-in-1 admixtures were evaluated over 2 to 9 days at 4°C and then 24 hours at 25°C in EVA bags. No substantial changes were noted in the fat particle sizes and no visual changes of emulsion breakage were observed. All admixtures tested had particle sizes in the 2- to 40-µm range.²⁴⁶⁵

The stability of 3-in-1 parenteral nutrition admixtures prepared with Vamin 14 with electrolytes and containing either Lipofundin MCT/LCT 20% or Intralipid 20% was evaluated. The admixtures contained 66.7 mmol/L of monovalent and 6.7 mmol/L of divalent cations. Stability of the lipid emulsion was evaluated after 2, 7, and 21 days at 4°C in EVA bags followed by 24 hours at room temperature to simulate infusion. Microscopy, Coulter counter, photon correlation spectroscopy, and laser diffractometry techniques were used to determine stability. Droplet size by microscopy was noted to increase to 18 to 20 µm after 21 days in both of the admixtures with the Intralipid-containing admixture showing particles this large as early as day 2 and with Lipofundin MCT/LCT at day 7. The Coulter counter assessed particles greater than 2 µm to be approximately 1300 to 1500 with Lipofundin MCT/LCT and 37,000 in the Intralipid-containing admixtures immediately after their preparation. Heavy creaming with a thick firm layer was noted after 2 days with the Intralipid-containing admixture, making particle assessment difficult. The authors concluded that storage limitation of 2 days for the Intralipid-containing admixture and not more than 7 days for the Lipofundin-containing admixture appeared justified. They also noted that calcium and magnesium behaved identically in destabilizing lipid emulsion with greater concentrations of divalent cations.⁸⁶⁷

The physical instability of 3-in-1 TNA stored for 24 hours at room temperature was reported. The admixtures intended for use in neonates and infants were compounded with TrophAmine 2 to 3%, dextrose 18 to 24%, Liposyn II (Abbott) 2 to 3%, L-cysteine hydrochloride, and the following electrolytes:

The emulsion in the admixtures cracked and developed visible free oil within 24 hours after compounding. The incompatibility was considered to create a clinically significant risk of complications if the admixture was administered. The authors determined that these 3-in-1 TNA containing these concentrations of electrolytes were unacceptable and should not be used.²⁶¹⁹

Another evaluation of 3-in-1 TNA reported physical instabilities of several formulations evaluated over 7 days. The parenteral nutrition admixtures were prepared with dextrose 15%, and Intralipos 4% (Fresenius Kabi) along with FreAmine 4.3%, NephrAmine 2.1%, TrophAmine 2.7%, Topanusol 5%, or HepatAmine 4%. Various electrolytes and other components were also present including sodium, potassium, calcium (salt form unspecified), magnesium, trace elements, vitamin K, and heparin. The admixtures were stored at 4°C and evaluated at 0, 3, and 7 days. After removal from refrigeration, the samples were subjected to additional exposure to room temperature and temperatures exceeding 28°C for 24 to 48 hours. Flocculation was found in the admixtures prepared with FreAmine and with TrophAmine after 24 hours of storage at room temperature and after 3 days under refrigeration followed by 24 hours at room temperature. All of the admixtures developed coalescence after 7 days under refrigeration followed by 24 hours at greater than 28°C.²⁶²¹

The physical stability of 5 highly concentrated 3-in-1 parenteral nutrition admixtures for fluid-restricted adults was evaluated. The admixtures were composed of Aminoplasmal (B. Braun) at concentrations over 7% as the amino acids source, dextrose concentrations of about 20%, and a 50:50 mixture of medium-chain triglycerides and long-chain triglycerides (Lipofundin MCT, B. Braun) at concentrations of about 2.5 to 2.7% as the lipid component with electrolytes and vitamins (TNA #269 through #273 in Appendix). The parenteral nutrition admixtures were prepared in EVA bags and stored at room temperature for 30 hours. Electronic evaluation of mean fat particle sizes and globule size distribution found little change over the 30-hour test period.²⁷²¹

The physical stability of 64 formulations of 3-in-1 parenteral nutrition admixtures containing Smoflipid 20% (TNA #277 in Appendix) and 16 formulations of 3-in-1 parenteral nutrition admixtures containing Lipoplus 20% (TNA #278 in Appendix), both in combination with fixed amounts of dextrose 40% and amino acids (Neonutrin 15%) and variable amounts of electrolytes, was evaluated.³²⁶¹ Admixtures were stored in EVA bags for up to 29 days at 2 to 8°C followed by 24 hours at 23 to 25°C.³²⁶¹ Particle counts were assessed by optical microscopy.³²⁶¹ Although particle counts increased over time in admixtures containing either lipid emulsion product, all admixtures remained stable throughout the study period and particle counts remained within limits.³²⁶¹ Formulations with Lipoplus 20% contained fewer large fat particles than those with Smoflipid 20%.³²⁶¹

The drop size of 3-in-1 parenteral nutrition solutions in drip chambers is variable, being altered by the constituents of the mixture. In one study, multivitamins (Multibionta, E. Merck) caused the greatest reductions in drop size, up to 37%. This change may affect the rate of delivery if flow is estimated from drops per minute.¹⁰¹⁶ Similarly, flow rates delivered by infusion controllers dependent on predictable drop size may be inaccurate. Flow rates up to 29% less than expected have been reported. Therefore, variable-pressure volumetric pumps, which are independent of drop size, should be used rather than infusion controllers.¹²¹⁵

When using multicomponent, 3-in-1, parenteral nutrition admixtures, the following points should be considered:⁴⁹⁰; ⁷⁰³; ⁸⁹²; ⁸⁹³; ¹⁰²⁵; ¹⁰⁶⁴; ¹⁰⁷⁰; ¹²¹⁴; ¹³²⁴; ¹⁴⁰⁶; ¹⁶⁷⁰; ²²¹⁵; ²²⁸²; ²³⁰⁸; ³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³⁴⁴⁴; ⁴⁰²⁷

1. The order of mixing is important. The amino acid solution should be added to the dextrose prior to addition of the lipid emulsion. This practice ensures that the protective effect of the amino acids to emulsion disruption by changes in pH and the presence of electrolytes is realized. Alternatively, some manufacturers of lipid emulsion state that all 3 components may be transferred to the admixture containers simultaneously, admixing with gentle agitation.
2. Electrolytes should not be added directly to the lipid emulsion. Instead, they should be added to the amino acids or dextrose before the final mixing.
3. Such 3-in-1 admixtures containing electrolytes (especially divalent cations) are unstable and will eventually aggregate. The mixed systems should be carefully examined visually before use to ensure that a uniform emulsion still exists and that separation of the emulsion (i.e., “breaking” or “oiling out”), indicated by yellowish streaking or accumulation of yellowish droplets in the admixed emulsion, has not occurred.
4. Avoid contact of 3-in-1 parenteral nutrition admixtures with heparin, which destabilizes and damages the lipid emulsion upon contact.
5. The admixtures should be stored under refrigeration if not used immediately.
6. The ultimate stability of the admixtures will be the result of a complex interaction of pH, component concentrations, electrolyte concentrations, and, probably, storage temperature.

Furthermore, a 1.2-µm filter should be used in the administration of lipid emulsion, intravenous, whether used alone or administered as a component of a TNA (3-in-1); filtration is necessary to remove large lipid particles, electrolyte precipitates, other solid particulates and aggregates.¹¹⁰⁶; ¹⁶⁵⁷; ¹⁷⁶⁹; ²⁰⁶¹; ²¹³⁵; ²³⁴⁶; ³²⁵¹; ³²⁵²; ³²⁵³; ³²⁵⁴; ³²⁵⁵; ³²⁵⁹; ³²⁶⁰; ³⁴⁴⁴; ⁴⁰²⁷

Heparin

Heparin sodium has been stated to be compatible in lipid emulsion.⁴⁸⁰; ⁶⁶⁰ The addition of heparin sodium (Abbott) 1 and 2 units/mL to Liposyn 10% and Intralipid 10% did not break the emulsion and effectively reversed the blood hypercoagulability associated with intravenous lipid emulsion administration.⁵⁶⁸ Heparin sodium (Fresenius Kabi) 500 units/mL mixed with Intralipid 20%, Nutrilipid 20%, or Smoflipid 20% in a 1:1 ratio was physically compatible (defined as the percentage of fat residing in globules larger than 5 microns [PFAT5] less than 0.05) for 4 hours at room temperature.³⁷⁶⁷; ³⁷⁶⁹

Flocculation of lipid emulsion (Kabi-Vitrum), however, has been reported during Y-site administration into a line used to infuse a parenteral nutrition solution containing both calcium gluconate and heparin sodium. Subsequent evaluation indicated that the combination of calcium gluconate (0.46 and 1.8 mmol/125 mL) and heparin sodium (25 and 100 units/125 mL) in amino acids plus dextrose induced flocculation of the lipid emulsion within 2 to 4 minutes at concentrations that resulted in no visually apparent flocculation in 30 minutes with either agent alone.¹²¹⁴

Calcium chloride quantities of 1 to 20 mmol normally result in slow flocculation of lipid emulsion 20% over several hours. When heparin sodium 5 units/mL was added, the flocculation rate was accelerated greatly and a cream layer was observed visually in a few minutes. This effect was not observed when sodium ion was substituted for the divalent calcium.¹⁴⁰⁶

Similar results were observed during simulated Y-site administration of heparin sodium into nine 3-in-1 nutrient admixtures having different compositions. Damage to the lipid emulsion component was found to occur immediately, with the possible formation of free oil over time.²²¹⁵

The destabilization of lipid emulsion (Intralipid 20%) when administered simultaneously with a TPN admixture and heparin was observed. The damage, detected by viscosity measurement, occurred immediately upon contact at the Y-site. The extent of the destabilization was dependent on the concentration of heparin and the presence of MVI Pediatric with its surfactant content. Additionally, phase separation was observed in 2 hours. The authors noted that TPN admixtures containing heparin should never be premixed with lipid emulsion as a 3-in-1 TNA because of this emulsion destabilization. The authors indicated their belief that the damage could be minimized during Y-site co-administration as long as the heparin was kept at a sufficiently low concentration (no visible separation occurred at a heparin concentration of 0.5 unit/mL) and the length of tubing between the Y-site and the patient was minimized.²²⁸²

However, because the damage to emulsion integrity has been found to occur immediately upon mixing with heparin in the presence of the calcium ions in TPN admixtures¹²¹⁴; ²²¹⁵; ²²⁸² and no evaluation and documentation of the clinical safety of using such destabilized emulsions has been performed, use of such damaged emulsions in patients is suspect.

Amphotericin B

In an effort to reduce toxicity, amphotericin B has been admixed in Intralipid instead of the more usual dextrose 5%.¹⁸⁰⁹; ¹⁸¹⁰; ¹⁸¹¹; ²¹⁷⁸ However, amphotericin B 0.75 mg/kg/day administered using this approach in 250 mL of Intralipid 20% has been associated with acute pulmonary toxicities, including sudden onset of coughing, tachypnea, agitation, cyanosis, and deterioration of oxygen saturation. The temporal relationship between the drug administration and respiratory symptoms suggested a causal relationship. Furthermore, no reduction in renal toxicity or other side effects associated with amphotericin B was observed. The authors concluded amphotericin B should not be administered to patients in Intralipid.²¹⁷⁷

At a concentration of 0.6 mg/mL in Intralipid 10 or 20%, amphotericin B precipitated immediately or almost immediately. The precipitate was not visible to the unaided eye because of the emulsion’s dense opacity. Particle size evaluation found thousands of particles larger than 10 µm per mL. In dextrose 5%, very few particles were larger than 10 µm. Centrifuging the Intralipid admixtures resulted in rapid visualization of the precipitate as a mass at the bottom of the test tubes.¹⁸⁰⁸

Amphotericin B precipitation is observed in lipid emulsion within 2 to 4 hours without centrifuging. In concentrations ranging from 90 mg/L to 2 g/L in Intralipid 20%, amphotericin precipitate is easily seen as yellow particulate matter on the bottom of the lipid emulsion containers.¹⁸⁷²; ¹⁹⁸⁸ Damage to the emulsion integrity with creaming also has been reported.¹⁹⁸⁷

In other reports, the appearance of problems was observed in as little as 15 minutes, and actual amphotericin B precipitate formed within 20 minutes of mixing. Analysis of the precipitate confirmed its identity as amphotericin B. The authors hypothesized that amphotericin B precipitates because the excipient deoxycholic acid, an anion, attracts oppositely charged choline groups from the egg yolk components of the lipid emulsion and forms a precipitate with phosphatidylcholine, leaving insufficient surfactant to keep the amphotericin B dispersed.²²⁰⁴; ²²⁰⁵

Plasma Expanders

Lipid emulsion (Abbott) 10 and 20% were combined with the plasma expanders Macrodex 6% in sodium chloride 0.9% (Schiwa), Gelafundin (Braun), Haes Steril 10% (Fresenius), and Expafusin Sine (Pfrimmer); fat particles exceeding 5 µm resulted, as observed by microscopic examination. These combinations were incompatible.¹⁶⁶⁸

For a list of references cited in the text of this monograph, search the monograph titled References.

ASHP^® Injectable Drug Information^TM. Selected Revisions December 5, 2024. © Copyright, 2024. American Society of Health-System Pharmacists^®, 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.