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

2. Disclosures
Kelly Roehl
No Disclosures

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

4. Objectives
Briefly describe current intravenous lipid emulsion (IVLE) formulations available in the United States.
Describe availability and the current state of literature regarding IVLEs, including potential benefits or drawbacks of non-standard formulations.
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.

5. What are lipids and why are they important?

6. Fatty Acid = Most Basic Form
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
Fatty Acid = Most Basic Form
Hydrocarbon ‘tail’ (hydrophobic)
Carboxyl ‘head’ (hydrophilic)

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

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

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

10. 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
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:

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

12. Biochemical Pathways
Lipids

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

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

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

16. Intravenous Lipid Emulsions (IVLEs)

17. Provide energy (2 kcal/mL)
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
% energy from α-linolenic acid
1 Mirtallo J et al. JPEN 2004;28:S39-S70.

18. Essential Fatty Acid Deficiency (EFAD)
Symptoms1
Scaly skin, impaired wound healing and immune function, death1
Triene-to-tetraene ratio >0.22
Prevention3
2-4% energy from linoleic acid
% energy from α-linolenic acid
1 Hansen AE et al. J Nutr. 1958;66: Holman R. Prog Chem Fats Other Lipids. 1971;9: Mirtallo J et al. JPEN 2004;28:S39-S70.

19. Fatty acids in form of triglycerides
Composition of IVLEs
Fatty acids in form of triglycerides
Designed to mimic chylomicrons ( 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

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

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

22. IVLEs in Human Body – Elevated TGsX X
+++
Mirtallo JM et al. Ann Pharmacother. 2010;44:

23. IVLEs in Human Body – Elevated TGsX
+++
Mirtallo JM et al. Ann Pharmacother. 2010;44:

24. History of IVLEs
Pharmaceutical-grade SO-based IVLE introduced2
OO-based IVLE introduced2
FO-based IVFE introduced2
MCT/LCT coconut/soy IVLE introduced2
Structured lipids introduced (MCT/LCT)3
First use of ILVE (olive oil +lecithin) in a child1
*Slide adapted from Todd Canada, Mandy Corrigan
Helfrick FW et al. J Pediatr. 1944;25: Vanek VW et al. Nutr Clin Pract. 2012;27: Osborn HT et al. Compr Rev Food Sci Food Safety. 2002;3:

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

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

27. Characteristics of SO-based IVLE
High omega 6 to omega 3 ratio1
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 EFAD2
2-4% energy from linoleic acid
% energy from α-linolenic acid
1 Intralipid Package Insert. Deerfield, IL: Baxter Healthcare Corporation; Mirtallo J et al. JPEN. 2004;28:S39-S70.

28. Why the Controversy with SO- ILVEs?
SO-based IVLE associated with:
Impaired immune function1,2
Inflammation2,3
Oxidative stress4
Cholestasis5,6
Until recently, only SO-based IVLEs have been available in the United States
1 Nordenstrom J et al. Am J Clin Nutr. 1979;32: Sedman P et al. JPEN. 1990;14: Jarstrand C et al. JPEN. 1978;2: Roche LD. Oxid Antioxid Med Sci. 2013;1: Clayton PT et al. Gastroenterology.1993;14: Kurvinen A et al. J Pediatr Gastroenterol Nutr. 2012;54:

29. Soybean Oil (SO)-Based IVLE
Increased TNF-α, IL-6, neutrophils1
Transient worsening of pulmonary function in ALI/ARDS patients2-6
Increased pulmonary shunt
Increased MPAP
Increased A-a oxygen gradient
Decreased PaO2/FiO2 ratio
IVLE doses >0.13 g/kg/hr = impaired RES function
Phytosterol and high omega-6 fatty acid content associated with PNALD7-8
1 Krogh-Madesn R et al. Am J Physiol Endocrinol Metab.2008;294:E371-E Venus B et al. Chest. 1989;95: Hwang T et al. Chest. 1990;97:
4 Mathru M et al. Chest. 1991;99: Suchner U et al. Crit Care Medi 2001;29: Seidner DL et al. JPEN. 1989;13: Kurvinen A et al. J Pediatr Gastroenterol Nutr. 2012;54: Kosters A et al. Semin Liver Dis. 2010;30:

30. 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 phytosterols1-3
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 IVLEs3-6
Lower phytosterol content
1 Iyer KR et al. J Pediatr Surg. 1998;33: Carter BA et al. Pediatr Res. 2007;62: El Kasmi KC et al. Sci Transl Medi 2013;5: Kurvinen A et al. J Pediatr Gastroenterol Nutr. 2012;54: Kosters A et al. Semin Liver Dis. 2010;30: Vanek VW et al. Nutr Clin Pract. 2012;27:

31. Olive Oil (OO)-Based IVLEs
Prospective, RCT comparing SO to OO-IVLE among critically ill patients1
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 patients2
No differences in mortality or ICU LOS
Significant reduction in duration of mechanical ventilation compared to SO-IVLE (P=0.01)
Prospective, multicenter ICU study3
Shorter ICU LOS (P<0.001), termination of mechanical ventilation while alive (P=0.02) among those receiving OO-IVLE compared to SO-IVLE
Lower concentrates of phytosterols, omega-6 fatty acids  Less risk for PNALD4-5
1 Umpierrez GE et al. Crit Care Med ;40: Manzanares W et al. Intesive Care Med. 2013;39: Edmunds CE et al. Crit Care Med. 2014;42: Kurvinen A et al. J Pediatr Gastroenterol Nutr. 2012;54: Kosters A et al. Semin Liver Dis. 2010;30:

32. Fish Oil (FO)-Based IVLE
Healthy volunteers, received FO-IVLE or placebo 24 and 48 hrs before injection of an endotoxin1
Decreased inflammatory response 2 hours after endotoxin injection
Lower temperature, TNF-α, ACTH, cortisol, norepinephrine
Minimal research available in the critically ill population
Absence of phytosterols and potential anti-inflammatory omega-3 fatty acids associated with reversal of PNALD2-3
1 Pluess TT et al. Intensive Care Med. 2007;33: El Kasmi KC et al. Sci Transl Medi 2013;5: Vanek VW et al. Nutr Clin Pract. 2012;27:

33. Practice Guidelines SCCM/A.S.P.E.N.1,2 ESPEN3
Withhold SO-based IVLE during first 7 days in ICU
Alternative IVLEs are safe and may be beneficial
ESPEN3
IVLEs are safe and should be provided to the critically ill
Alternative emulsions (OO and FO) may be beneficial
Canadian Critical Care Nutrition4
When IVLEs are indicated, choose those that reduce n-6 load
Insufficient data to provide recommendations on IVLE to replace n-6 rich emulsions
1 McClave SA et al. JPEN. 2009;33: Vanek VW et al. Nutr Clin Pract. 2012;27: Singer P et al. Clin Nutr. 2009;28: Dhaliwal R et al. Nutr Clin Pract. 2014;29:29-43.

34. Soybean Oil-Sparing Strategies1-4
Withhold SO-based IVLE for first 7 days in critically ill patients
Reduce dose of SO-based IVLE for those requiring short-term PN (<10 days)
<1 g IVLE/kg/day
<0.11 g/kg/hr (24 hour infusion), 0.15 g/kg/hr (cycled)
Consider use of alternative IVLE among those with PNALD or requiring long-term PN
Olive-oil based
Fish-oil based (requiring FDA and IRB approval)
1 McClave SA et al. JPEN. 2009;33: Hise M et al. The A.S.P.E.N. Adult Nutrition Support Cre Curriculum. 2nd ed. Silver Spring, MD: The American Society for Parenteral and Enteral Nutrition; 2012: Manzanares W et al. JPEN 2014;38: Xu Z et al. Nutrients. 2012;4:

35. IVLE – Conclusion
Infusion of IVLEs with high concentrations of omega- 6 fatty acids may result in a pro-inflammatory immunosuppressive state
Plant-based IVLEs contain phytosterols, which may contributed to development of PNALD
SO-based IVLEs contain the highest phytosterol concentrations
Practice guidelines recommend to limit administration of omega-6 fatty acids by practicing ‘soybean oil sparing strategies’

36. Discussion