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Kelly Roehl, MS, RD, LDN, CNSC Rush University Medical Center June 2015 Updates in Parenteral Lipid Formulations Science to Practice

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Disclosures 2 Kelly Roehl No Disclosures

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Session Description This session addresses the role of parenteral lipids on the nutritional and health status of the adult nutrition support population. 3

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Objectives 4 1.Briefly describe current intravenous lipid emulsion (IVLE) formulations available in the United States. 2.Describe availability and the current state of literature regarding IVLEs, including potential benefits or drawbacks of non-standard formulations. 3.Identify patient groups that may benefit from administration of alternative and specialized IVLE formulations, and describe strategies for judicious use of various formulations among patients requiring PN support.

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What are lipids and why are they important? 5

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What is a Lipid? Molecules soluble in organic solvents Functions: Source of energy (fatty acids thru B-oxidation) Provide vitamins Structural & metabolic functions within cell membranes, hormone production 6 Fatty Acid = Most Basic Form Hydrocarbon tail (hydrophobic)Carboxyl head (hydrophilic)

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Fatty Acids Basis for all other lipids Classification: Chain length Degree of saturation Location of double bonds 7

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Fatty Acid Classification Examples 8 Linoleic Acid (18:2, n-6) -Linolenic Acid (18:3, n-3) 18 Carbon chain length polyunsaturated Omega classification (location of first double bond from -end) end

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Common Fatty Acids 9 Calder PC et al. Intensive Care Med. 2010;36:735-749. Common NameChemical NameStructureDietary Source Capric Decanoic 10:0Coconut Lauric Dedecanoic 12:0Coconut Myristic Tetradecanoic 14:0Milk Palmitic Hexadecanoic 16:0milk, eggs, meat, cocoa butter Palmitoleic 9-Hexadecenoic 16:1, n-7Fish Steric Octadecanoic 18:0Milk, eggs, meat, cocoa butter Oleic 9-Octadecenic 18:1, n-9Milk, eggs, meat, cocoa butter, olives Linoleic 9,12-Octadeadienoic 18:2, n-6Seed oil, egg, meat, animal fat Arachidonic 5,8,11,14-Eicosatetraenoic 20:4, n-6Meat, eggs, algal oils Alpha-Linolenic 59,12,15-Octadecatrienoic 18:3, n-3Seed oils, green leaves, nuts Eicosapentanoic 5,8,11,14,17- Eicosapentaenoic 20:5, n-3Fish Docosapentaenoic 7,10,13,16,19- Docosapentaenoic 22:5, n-3Fish Docosahexaenoic 4,7,10,13,16,19- Docosahexaenoic 22:6, n-3Fish, algal oils

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Fatty Acids Chain Length Long-Chain Fatty Acids Triglycerides (LCTs) >14 carbons Medium Chain Fatty Acids Triglycerides (MCTs) 6-12 carbons Short-Chain Fatty Acids 2-4 carbons 10 American Diet >90% Palmitic acid (16:0), steric acid (18:0), oleic acid (18:1), and linoleic acid (18:2) Animal & plant fats/oils Butyric acid (4:0), lauric acid (12:0) and myristic acid (14:0) Milk fat & coconut oil Wanten GJ. Am J Clin Nutr. 2007;85:1171-84.

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Triglycerides Intravenous Lipid Emulsions (IVLEs) contain fatty acids in the form of triglycerides 11 3 Fatty Acids + Glycerol = Triglyceride

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Biochemical Pathways 12 Lipids

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Why is Lipid Origin Important? 13. 1 Helfrick FW et al. J Pediatr. 1944;25:400-403. 2 Vanek VW et al. Nutr Clin Pract. 2012;27:150-192 3 Osborn HT et al. Compr Rev Food Sci Food Safety. 2002;3:110-120. *Slide adapted from Todd Canada, Mandy Corrigan Fatty acid composition of cell membranes determines structural properties, regulatory and immune functions Incorporated into cell membranes impacting: Membrane fluidity Membrane fluidity Production of bioactive mediators Cell signaling Regulation of gene expression

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Fatty Acids, Inflammation, Immunoregulation 14 1 Vanek VW et al. Nutr Clin Pract. 2012;27:150-192.

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Fatty Acids, Inflammation, Immunoregulation 15 1 Vanek VW et al. Nutr Clin Pract. 2012;27:150-192. 2 Calder PC. Am J Clin Nutr. 2006;83:S1505-S1519. 3 Calder PC. Eur J Clin Nutr. 2002;56:S14-S19. Release of lysosomal enzymes Release of chemotactic agents Vascular permeability Vasodilation IL-6 production Fever Pain Impact of Pro-Inflammatory Eicosanoids

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Intravenous Lipid Emulsions (IVLEs) 16

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Why are IVLEs used? Provide energy (2 kcal/mL) Cellular beta-oxidation Provide fat-soluble vitamins Prevent essential fatty acid deficiency (EFAD) 2-4% energy from linoleic acid 0.25-0.5% energy from -linolenic acid 17 1 Mirtallo J et al. JPEN 2004;28:S39-S70.

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Essential Fatty Acid Deficiency (EFAD) Symptoms 1 Scaly skin, impaired wound healing and immune function, death 1 Triene-to-tetraene ratio >0.2 2 Prevention 3 2-4% energy from linoleic acid 0.25-0.5% energy from -linolenic acid 18 1 Hansen AE et al. J Nutr. 1958;66:565-576. 2 Holman R. Prog Chem Fats Other Lipids. 1971;9:275-348. 3 Mirtallo J et al. JPEN 2004;28:S39-S70.

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Composition of IVLEs Fatty acids in form of triglycerides Designed to mimic chylomicrons (200-500 nm) Type of FAs depends on source of lipid Emulsifier to enhance stability Egg yolk or lecithin Fat-soluble vitamins A, E, D, K Phytosterols Structurally similar to cholesterol 19

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IVLEs in Human Body 20 Mirtallo JM et al. Ann Pharmacother. 2010;44:668-700.

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IVLEs in Human Body 21 Mirtallo JM et al. Ann Pharmacother. 2010;44:668-700.

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IVLEs in Human Body Elevated TGs 22 X +++ X Mirtallo JM et al. Ann Pharmacother. 2010;44:668-700.

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IVLEs in Human Body Elevated TGs 23 X +++ Mirtallo JM et al. Ann Pharmacother. 2010;44:668-700.

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History of IVLEs 24 1944 1961 1984 1996 2000 2005 First use of ILVE (olive oil +lecithin) in a child 1 Pharmaceutical-grade SO-based IVLE introduced 2 MCT/LCT coconut/soy IVLE introduced 2 OO-based IVLE introduced 2 Structured lipids introduced (MCT/LCT) 3 FO-based IVFE introduced 2. 1 Helfrick FW et al. J Pediatr. 1944;25:400-403. 2 Vanek VW et al. Nutr Clin Pract. 2012;27:150-192 3 Osborn HT et al. Compr Rev Food Sci Food Safety. 2002;3:110-120. *Slide adapted from Todd Canada, Mandy Corrigan

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25 Furhman T. Support Line. 2014;36(6):27-28.

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IVLEs Available Internationally 26 Furhman T. Support Line. 2014;36(6):27-28. Calder PC et al. Intensive Care Med. 2010;36:735-749. ProductSourceFDA Approved Under FDA Approval Not Available in US Intralipid 20% (Fresenius Kabi/Baxter) 100% soy X Liposyn III 20% (Hospira) 100% soy X Nutrilipid 20% (B Braun) 100% soy X ClinOleic 20% (Baxter) 80% olive, 20% soy X SMOF 20% (Fresenius Kabi) 30% coconut, 30% soy, 25% olive, 15% fish X Omegaven 10% (Fresenius Kabi) 100% fish*compassionate use only Lipofundin 20% (B Braun) 50% coconut, 50% soy X Structolipid 20% (Fresenius Kabi) 36% coconut, 64% soy X Lipoplus 20% (B Braun) 50% coconut, 40% soy, 10% fish X

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Characteristics of SO-based IVLE High omega 6 to omega 3 ratio 1 44-62% linoleic acid (n-6) 4-11% alpha-linolenic acid (n-3) Typical dosing strategies for SO-based IVLE: 15-30% total kcal, although only very low doses would be necessary to prevent EFAD 2 2-4% energy from linoleic acid 0.25-0.5% energy from -linolenic acid 27 1 Intralipid Package Insert. Deerfield, IL: Baxter Healthcare Corporation; 2006. 2 Mirtallo J et al. JPEN. 2004;28:S39-S70.

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Why the Controversy with SO- ILVEs? SO-based IVLE associated with: Impaired immune function 1,2 Inflammation 2,3 Oxidative stress 4 Cholestasis 5,6 Until recently, only SO-based IVLEs have been available in the United States 28 1 Nordenstrom J et al. Am J Clin Nutr. 1979;32:2416-2422. 2 Sedman P et al. JPEN. 1990;14:12-17. 3 Jarstrand C et al. JPEN. 1978;2:663-670. 4 Roche LD. Oxid Antioxid Med Sci. 2013;1:11-14. 5 Clayton PT et al. Gastroenterology.1993;14:158-164. 6 Kurvinen A et al. J Pediatr Gastroenterol Nutr. 2012;54:803-811.

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Soybean Oil (SO)-Based IVLE Increased TNF-, IL-6, neutrophils 1 Transient worsening of pulmonary function in ALI/ARDS patients 2-6 Increased pulmonary shunt Increased MPAP Increased A-a oxygen gradient Decreased PaO 2 /FiO 2 ratio IVLE doses >0.13 g/kg/hr = impaired RES function Phytosterol and high omega-6 fatty acid content associated with PNALD 7-8 29 1 Krogh-Madesn R et al. Am J Physiol Endocrinol Metab.2008;294:E371-E379. 2 Venus B et al. Chest. 1989;95:1278-12181. 3 Hwang T et al. Chest. 1990;97:934-948. 4 Mathru M et al. Chest. 1991;99:426-429. 5 Suchner U et al. Crit Care Medi 2001;29:1569-1574. 6 Seidner DL et al. JPEN. 1989;13:619-619. 7 Kurvinen A et al. J Pediatr Gastroenterol Nutr. 2012;54:803-811. 8 Kosters A et al. Semin Liver Dis. 2010;30:186-194.

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Phytosterols & PNALD IVLE associated with cholestasis (PNALD) Pro-inflammatory omega-6 concentration Phytosterols IV phytosterols bypasses the initial hepatic elimination leading to high concentrations of serum phytosterols 1-3 Inhibition of FXR, resulting in reduced bile acid and bilirubin excretion, damage to the hepatocyte Improved liver enzymes with infusion of OO-and FO- based IVLEs 3-6 Lower phytosterol content 30 1 Iyer KR et al. J Pediatr Surg. 1998;33:1-6. 2 Carter BA et al. Pediatr Res. 2007;62:301-306. 3 El Kasmi KC et al. Sci Transl Medi 2013;5:1-10. 4 Kurvinen A et al. J Pediatr Gastroenterol Nutr. 2012;54:803-811. 5 Kosters A et al. Semin Liver Dis. 2010;30:186-194. 6 Vanek VW et al. Nutr Clin Pract. 2012;27:150-192.

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Olive Oil (OO)-Based IVLEs Prospective, RCT comparing SO to OO-IVLE among critically ill patients 1 No differences in complications, glycemic control, inflammatory or oxidative stress markers, immune function, hospital or ICU LOS Systematic review of alternative IVLEs among critically ill patients 2 No differences in mortality or ICU LOS Significant reduction in duration of mechanical ventilation compared to SO-IVLE (P=0.01) Prospective, multicenter ICU study 3 Shorter ICU LOS (P