Fresenius Kabi received approval from FDA in July 2016 for Smoflipid®, a four-oil IV fat emulsion (IVE), available in the USA for adult patients. This IV fat emulsion product has been used for many years in other global markets and contains soybean oil, medium chain triglycerides, olive oil, and fish oil.   This is an exciting development since in the USA, there has been only been two approved products that are primarily soybean oil based.   Intralipid® by Baxter is 100% soybean oil based, and Clinolipid® by Baxter is 20% soybean oil and 80% Olive oil (1).

IV lipids are needed to provide additional non-protein calories, less metabolic complications than fat free total parenteral nutrition (TPN), and soybean oil intravenous lipid emulsion (ILE) also contain robust amounts of essential fatty acids, linoleic acid, and α-linolenic acid (1).   Minimal parenteral nutrition (PN) requirements of linoleic acid to prevent Essential Fatty Acid Deficiency have been estimated to be at least 1% of total calories, with optimal levels being 3-4%, whereas α-linolenic acid requirements are even less at 0.2-0.5% of total calories (1,2,3).  A typical composition ILE is 10-30% soybean oil, 1.2% egg yolk phospholipids, and 2.25% glycerin with calorie content ranging from 10- 11 kcal/g depending on concentration (4,5).  Therefore, ILE provide an excellent source of calories allowing for a reduction in the amount of dextrose used in parenteral nutrition (1).

Despite these benefits, the high ratio of n-6 to n-3 polyunsaturated fatty acids (PUFA) in soybean ILE can have adverse effects.  These fatty acids are used to make byproducts including arachidonic acid (AA) and eicosapentaenoic (EPA) and docosahexaenoic (DHA) (3,4).  Arachidonic Acid can be further metabolized to give rise to pro-inflammatory eicosanoids.  On the other hand, EPA, which originates from n-3 PUFAs, tends to generate less pro-inflammatory 3-series prostaglandins and thromboxanes (1). Soybean oil ILE can also lead to increased LDL and triglyceride levels as well as a decrease in HDL levels (1).

Another common complication of parental nutrition (PN) is intestinal failure associated liver disease (IFALD) affecting 30-60% of children and 15-40% of adults requiring long-term soybean oil ILE (4).  IFALD tends to vary in clinical presentation and can include hepatic steatosis, cholestasis, cholelithiasis, and hepatic fibrosis (6).

Numerous studies have shown significant improvement or reversal of intestinal failure associated liver disease (IFALD) with the use of fish oil ILE in the pediatric and adult population (7,8). Heller et al. studied the impact of combining fish oil (0.2 g/kg/day Omegaven®) with soybean oil (0.8g/kg/day of 10% Lipovenoes®) versus soybean oil alone (10% Lipovenoes®) in 44 post abdominal surgery patients and noted that the combination of fish oil with soybean oil resulted in significant decrease in liver enzymes and bilirubin levels (9).   Klek et al. conducted a trial randomizing patients with stable intestinal failure to either Smoflipid® or soybean oil ILE (Intralipid®) and noted that mean ALT, AST, and total bilirubin concentrations were significantly lower in the Smoflipid® group (10).   The fish oil ILE’s tend to have higher levels of α-tocopherol (~200mg/L) raising plasma concentrations compared to soybean oil ILE (10, 11).  Α-tocopherol is an antioxidant from the Vitamin E family, that is capable of scavenging free radicals (12).   In addition to raising α-tocopherol concentrations, patients receiving fish oil ILEs also tend to have lower n-6 PUFA and higher n-3 PUFA concentrations, producing a less pro-inflammatory profile (11).  Metry et al. noted a significantly lower IL-6 level in surgical ICU patients randomized to Smoflipid® compared to Intralipid® on both day 4 and 7 of the trial (13).

Beyond these liver and anti-inflammatory benefits, studies have also revealed metabolic benefit as patients randomized to Lipoplus® had a greater reduction in free-fatty acids, smaller rise in triglyceride levels, and less reduction in HDL after ~7 days of use compared to the Lipofundin® group(1, 14).  Wu et al. also noted lower triglyceride levels on day 6 in patients randomized to Smoflipid® versus Lipovenoes®.(15)

Of note, most of these trials are very short term and further studies on the long-term impact of fish oil ILE needs to be evaluated (1). One area of concern is the development of EFAD given the lower ratio of n-6 PUFAs (1).   An important contributor to the lack of essential fatty acid deficiency (EFAD) with fish oil ILE may be their higher content of amino acids, which is typically derived from linoleic acid (16).  Take into consideration when choosing ILE product the FDA contraindications for Smoflipid®:  known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients; severe hyperlipidemia or disorders of lipid metabolism with serum triglycerides > 1,000 mg/dL. (17).  FDA prescribing label information states that the usual daily dosage in adults is 1 to 2 grams/kg per day and should not exceed 2.5 grams/kg per day (17).

 

References

  1. Mundi M, Salonen B, Bonnes S, et al. Parenteral Nutrition-Lipid Emulsions and Potential Complications.  Prac Gastro.  August 2017, pg 32-37.
  2. Gramlich L, Meddings L, Alberda C, et al. Essential Fatty Acid Deficiency in 2015 The Impact of Novel Intravenous Lipid Emulsions. J Parenter Enter Nutr. 2015;39(1 suppl):61S-66S.
  3. Bistrian BR. Clinical aspects of essential fatty acid metabo­lism: Jonathan Rhoads Lecture. JPEN J Parenter Enteral Nutr. 2003;27(3):168-175.
  4. Mundi MS, Salonen BR, Bonnes S. Home Parenteral Nutrition Fat Emulsions and Potential Complications. Nutr Clin Pract. August 2016:884533616663635.
  5. Vanek VW, Seidner DL, Allen P, et al. A.S.P.E.N. Position Paper Clinical Role for Alternative Intravenous Fat Emulsions. Nutr Clin Pract. 2012;27(2):150-192.
  6. Kelly DA. Intestinal Failure–Associated Liver Disease: What Do We Know Today? Gastroenterology. 2006;130(2, Supplement):S70-S77.
  7. Premkumar MH, Carter BA, Hawthorne KM, et al. Fish Oil– Based Lipid Emulsions in the Treatment of Parenteral Nutrition- Associated Liver Disease: An Ongoing Positive Experience123. Adv Nutr. 2014;5(1):65-70
  8. Burns DL, Gill BM. Reversal of Parenteral Nutrition–Associated Liver Disease With a Fish Oil–Based Lipid Emulsion (Omegaven) in an Adult Dependent on Home Parenteral Nutrition. J Parenter Enter Nutr. 2013;37(2):274-280.
  9. Heller AR, Rössel T, Gottschlich B, et al. Omega-3 fatty acids improve liver and pancreas function in postoperative cancer patients: Omega-3 Fatty Acid After Cancer Surgery. Int J Cancer. 2004;111(4):611-616.
  10. Klek S, Chambrier C, Singer P, et al. Four-week parenteral nutri­tion using a third generation lipid emulsion (SMOFlipid) – A double-blind, randomised, multicentre study in adults. Clin Nutr. 2013;32(2):224-231.
  11. Dai Y-J, Sun L-L, Li M-Y, et al. Comparison of Formulas Based on Lipid Emulsions of Olive Oil, Soybean Oil, or Several Oils for Parenteral Nutrition: A Systematic Review and Meta-Analysis. Adv Nutr Bethesda Md. 2016;7(2):279-286.
  12. Brigelius-Flohé R. Bioactivity of vitamin E. Nutr Res Rev. 2006;19(2):174-186.
  13. Metry AA, Abdelaal W, Ragaei M, et al. SMOFlipid versus Intralipid in Postoperative ICU Patients. Enliven J Anesth Crit Care Med. 2014;1(6):15.
  14. Ma C-J, Wu J-M, Tsai H-L, et al. Prospective double-blind randomized study on the efficacy and safety of an n-3 fatty acid enriched intravenous fat emulsion in postsurgical gastric and colorectal cancer patients. Nutr J. 2015;14.
  15. Wu M-H, Wang M-Y, Yang C-Y, et al. Randomized Clinical Trial of New Intravenous Lipid (SMOFlipid 20%) Versus Medium- Chain Triglycerides/Long-Chain Triglycerides in Adult Patients Undergoing Gastrointestinal Surgery. J Parenter Enter Nutr. 2014;38(7):800-808.
  16. Strijbosch RAM, Lee S, Arsenault DA, et al. Fish oil prevents essential fatty acid deficiency and enhances growth: clinical and biochemical implications. Metabolism. 2008;57(5):698-707.
  17. SMOFLIPID (lipid injectable emulsion): full prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207648lbl.pdf accessed 10/22/18.