Since about 1975, soybean oil-based intravenous lipid injectable emulsions (SO-ILEs) have been the main source of fats for patients receiving parenteral nutrition (PN), with a standard dosing recommendation of up to 1 g/kg/d of SO-ILE for adults.1 However, this method is not an infallible nutrition solution—SO-ILEs are thought to be directly related to many hepatobiliary complications, and PN itself requires an individually tailored approach for each patient.1 This, along with ILE shortages across the pharmaceutical industry, compelled the American Society of Parenteral and Enteral Nutrition (ASPEN) to urge the pharmaceutical industry to bring new ILEs to market.
Following this appeal, there are now four different formulations of ILEs, with different dosages and safety considerations for each. It is crucial to understand differences between products and to establish updated prescribing practices. While guidance on this has been provided with the release of the ASPEN’s consensus recommendations, ASPEN Lipid Injectable Emulsion Safety Recommendations, Part 1: Background and Adult Considerations, the selection of ILE products and defined dosing regimens are beyond the scope of that publication.2 Choosing which products to add to formulary or prescribe must start with basic understanding of lipids, history of the ILE market, and available products. Further, safe utilization of these products requires an understanding of indications, dosing, and administration requirements.
While ILE is an essential part of PN treatment (see the SIDEBAR), it is not without risks. Among these is the development of hepatobiliary dysfunction (PN-related liver disease, or PNALD) and/or intestinal failure-associated liver disease (IFALD).3,4,5 Polyunsaturated fatty acids (PUFA) and phytosterols present in ILE and long term PN are contributing risk factors for PNALD, while PN therapy, intestinal failure, and inflammation increase the risk of IFALD.3,4 Phytosterols, present in ILE, are phytosteroids that are commonly found in plant-based sources of oils and have a similar structure to cholesterol.6,7 When ingested enterally, phytosterols are about 1% to 5% absorbed, but if provided via the parenteral route then they are 100% bioavailable, potentially leading to cholestasis.6
Phospholipids are also sometimes added as an emulsifier to ILEs (usually egg phosphatide), which can sometimes produce liposomes called lipoprotein-X which interferes with triglyceride metabolism leading to hypertriglyceridemia.2 Additionally, the PUFAs found in ILEs contain multiple double bonds that are susceptible to peroxidation by free radicals in the body, which produce highly reactive lipid peroxide radicals.4,8,9 This chain reaction and the radicals it produces are destructive to cells.2 However, tocopherol is a natural component of oils that may be present in ILE products and can help prevent peroxidation of PUFAs.4 Each oil contains different amounts and types of tocopherols (alpha, beta, gamma, or alpha isoforms).8 Alpha-tocopherol has the most biological activity against peroxidation and fish oil contains the highest amount.4,8 Soybean oil contains gamma-tocopherol, which has 10% of the biological activity of alpha-tocopherol. The type and quantity of tocopherol is a vital component of the ILEs containing PUFAs, as provision of tocopherol stops the peroxide radical chain reaction.8
The Evolution of ILEs
Newer ILE products have focused on mitigating risks by providing ILEs with less pro-inflammatory omega-6 linoleic acid (LA) content, a lower omega-6 to omega-3 ratio, more alpha-tocopherol, and less phytosterols (see the FIGURE). In the 1980s, the second generation of ILEs focused on reducing the LA content of ILEs by physically mixing medium chain triglycerides (MCTs) from coconut oil with long chain triglycerides (LCTs) from soybean oil to form MCT/LCT ILE.8 This formulation contained less phytosterols and LA and provided immune neutral MCT oil.8 However, MCTs have less tocopherol and are hydrolyzed faster than PUFAs, which may cause serum hypertriglyceridemia, ketone bodies, and elevated insulin levels.8
To avoid high blood levels of medium-chained fatty acids, structured triglycerides were developed. Medium-chained fatty acids and long-chain fatty acids were bound to the same glycerol backbone.8 The structured lipid emulsions were hydrolyzed even quicker than the MCT/LCT physical mixture ILEs.8 Studies found that structured MCT/LCT ILEs produced increased ketone metabolites compared to physical MCT/LCT ILEs.8 The structured MCT/LCT ILEs contain lower alpha-tocopherol and higher phytosterols compared to physical MCT/LCT and are not available in the United States.8
In the 1990s, the third generation of ILEs were designed to provide omega-9 fatty acids from olive oil (OO) mixed with SO-ILEs. A mixture must be provided as oleic acid is not an essential fatty acid, but it does provide a source of energy and contains more alpha-tocopherol. In addition, oleic acid will compete with enzymes in the omega-3 pathway when there is less LA available and thus decrease the pro-inflammatory products of that pathway.2
The fourth generation of ILEs, developed in the 2000s, continued to provide less LA content and lowered the omega-6 to omega-3 PUFA ratio by the addition of fish oil (FO) to the formulation.2 These changes would promote the production of less pro-inflammatory cytokines and more anti-inflammatory cytokines.8 Omega-3 PUFAs are at a higher risk of susceptibility to oxidation because of the unsaturation level of these fatty acids, especially EPA and DHA so larger amounts of alpha-tocopherol are added.8
Currently, there are four different types of ILEs (SO-; OO, SO-; SO, MCT, OO, FO-; FO-ILE) with different dosing recommendations (see TABLE 1) and oil combinations which may benefit a particular patient population. However, all have some common key steps for administration (see TABLE 2). ASPEN and the Society of Critical Care Medicine (SCCM) have provided some guidance on the use of all four mixtures, and recent expert consensus statements made during the 2018 Lipid in Parenteral Nutrition summit were designed to bridge the gap that existed between the 2016 SCCM/ASPEN Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient and currently available ILE products, with potentially better outcomes for patients.
The consensus statements recognize that FO-ILEs can be utilized in critically ill patients, and ILEs containing FO do not need to be held during first week of therapy in unstable, critically ill patients.10 They also recommend utilizing FO-ILEs over ILEs without FO in adult surgical patients and those on home parenteral nutrition who are at risk for liver complication.10 The studies available that examine FO-ILE with low LA are promising but are limited to children, and there are concerns for development of essential fatty acid deficiency (EFAD) with use of this product.12 At present, it is uncertain whether providing individuals with essential fatty acid metabolites would prevent EFAD, and thus ILE dosage recommendations for mixed oil ILEs may be greater than SO-ILE dose recommendations of 1g/kg/d.
To decrease the risk of IFALD in long-term PN patients receiving SO-ILE, the dose of SO-ILE should not exceed 1 g/kg/d.10 The total energy supplied by ILE should range from 15% to 30% and the non-protein energy supplied by ILE should range from 30% to 50%.4 All patients with IFALD should be evaluated to ensure that they are not being overfed. Overfeeding leads to hepatic fat deposition through insulin release which promotes lipogenesis and fatty acid oxidation inhibition. Other strategies to mitigate IFALD include using cyclic parenteral nutrition, avoiding hepatoxic agents, and quick treatment and avoidance of sepsis.4 Those with IFALD, or an elevated risk for developing IFALD, should be considered for an ILE product with a lower ratio of omega-6 PUFA to omega-3 PUFA.2 If SO-ILE is provided, then the infusion rate should not be greater than 0.11 g/kg/hr.2 High infusion rates have been associated with hypertriglyceridemia, infectious complications, and fat overload syndrome.6
ILEs provide energy and essential fatty acids, and the risk of complications can be reduced through careful use. A thorough understanding of both the product components and potential patient-specific indications is imperative for providing safe and effective PN. Policies and procedures need to be in place for PN provision and, due to new products and expert recommendations, PN can and should be a personalized treatment.
Bridget Stefanski, PharmD, is a clinical pharmacy specialist in nutrition support at Covenant Healthcare in Saginaw, Michigan. She received her BS in pharmacy at Ferris State University and her PharmD from Ohio Northern University. Bridget is currently pursuing her master of science in nutrition and dietetics at Central Michigan University.
Formulation of ILEs
While PN is a life-saving treatment, it comes with inherent risks. One such risk is a deficiency of fatty acids, which can be mitigated when ILEs are present.8 Because of this, it is important to understand the role of lipids and their importance in total PN therapy.
Triglycerides, the source of lipids contained in ILEs, are broken by the body into glycerol and free fatty acids.9 The fatty acids may be used for energy, stored as a future energy source, converted into eicosanoids, or incorporated into cell membranes.6 The structure of a fatty acid consists of a hydrocarbon chain with a carboxyl group at one end and a methyl group at the other end.6 They are classified by the length of the hydrocarbon chain, presence or absence of double bonds, and location of the double bond(s).6
Saturated fatty acids have no double bonds, while monounsaturated fatty acids (MUFAs) contain a single double bond, and polyunsaturated fatty acids (PUFAs) contain multiple double bonds.6 Most naturally occurring triglycerides contain mixtures of different types of fatty acids bonded to a glycerol backbone.8 Fats from animal sources tend to contain large amounts of saturated fatty acids. Plant-derived fats have more unsaturated fats, and meat from marine animals contain the most unsaturated fatty acids.
The original triglyceride ingested will be transformed by shortening and lengthening the fatty acid hydrocarbon chain depending on what the body needs. Most fatty acids can be synthesized except for two long-chain fatty acids, linoleic acid (LA) and alpha-linolenic acid (ALA).4 These two fatty acids are the base components for eicosanoid production; therefore, LA and ALA or their derivatives must be consumed as part of the diet for normal growth and cellular metabolism and are considered essential fatty acids (EFAs).10
Essential fatty acid deficiency (EFAD) may occur if individuals do not receive an adequate amount of LA and ALA.11 For the prevention of EFAD, 1% to 4% of total energy requirements must be provided by LA and 0.25% to 0.5% of total energy requirement must be provided by ALA.11 EFAD can develop within 1 to 3 weeks for patients receiving fat-free PN.
Provision of certain types of fatty acids not only affects the eicosanoid mediators produced but can affect biological processes in other ways as well. They may be incorporated into phospholipids for cell membranes, act as cell signaling messengers, serve to regulate gene expression, and influence the structure of lipid rafts in cell membranes. Additionally, liver complications can occur due to a deficiency of essential fatty acids.4