Updates in Parenteral Lipid
Formulations – Science to Practice
Kelly Roehl, MS, RD, LDN, CNSC
Rush University Medical Center
June 2015
Disclosures
Kelly Roehl
No Disclosures
2
Session Description
This session addresses the role of parenteral
lipids on the nutritional and health status of
the adult nutrition support population.
3
Objectives
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.
4
What are lipids and
why are they important?
5
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)
6
Fatty Acids
Basis for all other lipids
Classification:
•
Chain length
•
Degree of saturation
•
Location of double bonds
7
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)
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Common Fatty Acids
Common Name
Chemical Name
Structure Dietary Source
Capric
Decanoic
10:0
Coconut
Lauric
Dedecanoic
12:0
Coconut
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
5,8,11,14,17Eicosapentaenoic
20:5, n-3
Fish
Docosapentaenoic
7,10,13,16,19Docosapentaenoic
22:5, n-3
Fish
Docosahexaenoic
4,7,10,13,16,19Docosahexaenoic
22:6, n-3
Fish, algal oils
Calder PC et al. Intensive Care Med. 2010;36:735-749.
9
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;85:1171-84.
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Triglycerides
3 Fatty Acids + Glycerol = Triglyceride
Intravenous Lipid Emulsions (IVLEs) contain fatty
acids in the form of triglycerides
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Biochemical Pathways
Lipids
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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
.
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.
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Fatty Acids, Inflammation, Immunoregulation
1 Vanek
VW et al. Nutr Clin Pract. 2012;27:150-192.
14
Fatty Acids, Inflammation, Immunoregulation
Impact of Pro-Inflammatory Eicosanoids
•
•
•
•
•
• Fever
• Pain
Release of lysosomal enzymes
Release of chemotactic agents
Vascular permeability
Vasodilation
IL-6 production
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.
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Intravenous Lipid Emulsions (IVLEs)
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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 α-linolenic acid
1 Mirtallo
J et al. JPEN 2004;28:S39-S70.
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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
• 0.25-0.5% energy from α-linolenic acid
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
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IVLEs in Human Body
Mirtallo JM et al. Ann Pharmacother. 2010;44:668-700.
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IVLEs in Human Body
Mirtallo JM et al. Ann Pharmacother. 2010;44:668-700.
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IVLEs in Human Body – Elevated TGs
X
X
+++
Mirtallo JM et al. Ann Pharmacother. 2010;44:668-700.
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IVLEs in Human Body – Elevated TGs
X
+++
Mirtallo JM et al. Ann Pharmacother. 2010;44:668-700.
23
History of IVLEs
1944
1961
1984
Pharmaceutical-grade
SO-based IVLE
introduced2
1996
OO-based IVLE
introduced2
MCT/LCT coconut/soy
IVLE introduced2
2000
2005
FO-based IVFE
introduced2
Structured lipids
introduced (MCT/LCT)3
First use of ILVE (olive
oil +lecithin) in a child1
*Slide adapted from
Todd Canada, Mandy Corrigan
.
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.
24
Furhman T. Support Line. 2014;36(6):27-28.
25
IVLEs Available Internationally
Product
Source
FDA Approved
Intralipid 20%
100% soy
X
100% soy
X
100% soy
X
80% olive, 20% soy
X
Under FDA
Approval
Not Available
in US
(Fresenius Kabi/Baxter)
Liposyn III 20%
(Hospira)
Nutrilipid 20%
(B Braun)
ClinOleic 20%
(Baxter)
(Fresenius Kabi)
30% coconut, 30% soy,
25% olive, 15% fish
Omegaven 10%
100% fish
SMOF 20%
(Fresenius Kabi)
Lipofundin 20%
X
*compassionate
use only
50% coconut, 50% soy
X
36% coconut, 64% soy
X
50% coconut, 40% soy,
10% fish
X
(B Braun)
Structolipid 20%
(Fresenius Kabi)
Lipoplus 20%
(B Braun)
Furhman T. Support Line. 2014;36(6):27-28.
Calder PC et al. Intensive Care Med. 2010;36:735-749.
26
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
0.25-0.5% energy from α-linolenic acid
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 function1,2
• Inflammation2,3
• Oxidative stress4
• Cholestasis5,6
Until recently, only SO-based IVLEs have been
available in the United States
1 Nordenstrom
4 Roche
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.
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-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-E379. 2 Venus B et al. Chest. 1989;95:1278-12181. 3 Hwang T et al. Chest. 1990;97:934-948.
5 Suchner U et al. Crit Care Medi 2001;29:1569-1574.
6 Seidner DL et al. JPEN. 1989;13:619-619.
M et al. Chest. 1991;99:426-429.
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.
4 Mathru
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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
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 FObased IVLEs3-6
•
1 Iyer
Lower phytosterol content
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.
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.
4 Kurvinen
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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
4 Kurvinen
GE et al. Crit Care Med. 2012;40:1792-1798. 2 Manzanares W et al. Intesive Care Med. 2013;39:1683-1694.
A et al. J Pediatr Gastroenterol Nutr. 2012;54:803-811. 5 Kosters A et al. Semin Liver Dis. 2010;30:186-194.
3
Edmunds CE et al. Crit Care Med. 2014;42:1168-1172.
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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 antiinflammatory omega-3 fatty acids associated with
reversal of PNALD2-3
1 Pluess
TT et al. Intensive Care Med. 2007;33:789-797.
2 El
Kasmi KC et al. Sci Transl Medi 2013;5:1-10.
3
Vanek VW et al. Nutr Clin Pract. 2012;27:150-192.
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Practice Guidelines
SCCM/A.S.P.E.N.1,2
• 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
4
2 Vanek VW et al. Nutr Clin Pract. 2012;27:150-192.
SA et al. JPEN. 2009;33:277-316.
Dhaliwal R et al. Nutr Clin Pract. 2014;29:29-43.
3
Singer P et al. Clin Nutr. 2009;28:387-400.
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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
•
•
1 McClave
Olive-oil based
Fish-oil based (requiring FDA and IRB approval)
SA et al. JPEN. 2009;33:277-316.
for Parenteral and Enteral Nutrition; 2012:63-82.
2 Hise
3
M et al. The A.S.P.E.N. Adult Nutrition Support Cre Curriculum. 2nd ed. Silver Spring, MD: The American Society
Manzanares W et al. JPEN 2014;38:653-654.
Xu Z et al. Nutrients. 2012;4:904-921.
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IVLE – Conclusion
Infusion of IVLEs with high concentrations of omega6 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’
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Discussion
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