Yohanes George

NEW LIPID ELUSION AND OUTCOME

IN CRITICALLY ILL PATIENTS

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 WHICH LIPID?

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 SEPSIS THERAPY
Bacterial sepsis

Exotoxin LPS/endotoxin Mediators

Antibiotics/surgical drainage General ICU support IMMUNOMODULATION

Monoclonal Antibodies Other anti-inflammatories

Steroids
- high dose
- low dose

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 IMMUNOHOMEOSTASIS
Bacterial sepsis

Exotoxin LPS/endotoxin Mediators

Antibiotics/surgical drainage General ICU support IMMUNOMODULATION

Monoclonal Antibodies Steroids Other anti-inflammatories

- high dose
- low dose

Mediator Adsorption/Removal
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 IMMUNOHOMEOSTASIS

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 FATTY ACIDS MAY ALTER IMMUNE
AND INFLAMMATORY PHENOTYPE1
FAs

Incorporation into cell

membranes

Oxidant
Penetrate into cell production
Membrane structure
and function
▪ Fluidity Gene expression
▪ Ion channels (eg, inflammatory gene
▪ Receptors expression via NF-kB)

Eicosanoid (and cytokine)

Cell signaling
production
FA, fatty acid; NF-kB, nuclear factor-kB.
Figure created using information obtained, in part, from Reference 1.
6 1. Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):1171-1184.
 IMMUNONUTRITION IN
TWO-PHASE-MODEL OF SEPSIS:
DIFFERENT THERAPEUTICAL INTERVENTIONS

GLN -3 -3?

ARG GLN ?
Immunoreaction

SEPSIS
IL-6
IL-8
Hyper-
inflamation IL-1 LPS induced
HLA-DR TNF-  release
TNF

IL-10 TGF-
Immuno-
paralysis IL-4
7 IL-13
 WHICH NUTRIENT FOR WHICH
POPULATION?
Elective Critically Ill
Surgery
General Septic Trauma Burns Acute Lung
Injury

Arginine Benefit No benefit Harm(?) (Possible No No

benefit) benefit benefit
Glutamine Possible PN … EN EN …
Benefit Beneficial Possibly Possibly
Beneficial: Beneficial:
Recom-
Consider Consider
mend

Omega 3 … … … … … Recom-
FFA mend

Anti- … Consider … … … …
oxidants

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Canadian Clinical Practice Guidelines JPEN 2003;27:355
 FATTY ACID CLASSIFICATION

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 FATTY ACID CLASSIFICATION

FA MAY BE CLASSIFIED ACCORDING TO 3

CHARACTERISTICS:
1. Degree of saturation: presence and number of double bonds
2. Omega (w) classification: position of the first double bond
relative to the non-carboxylic (ie, methyl) end of the carbon chain
3. Chain length: the number of carbons

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 FATTY ACID CLASSIFICATION:
SATURATION
Stearic acid

 Saturated FAs (SFAs): no

double bonds in carbon chain

Oleic acid
 Monounsaturated FAs
(MUFAs): 1 double bond in
carbon chain
Linoleic acid

 Polyunsaturated FAs (PUFAs):

≥2 double bonds in carbon
chain

11 Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):1171-1184.

 FATTY ACID CLASSIFICATION:
SATURATION

SFAs PUFAs MUFAs

• Most FAs in coconut oil1
• Increased risk of CV disease2
• Acute adverse effects include
endothelial
toxicity, apoptosis,
and inflammation3,4
• Should be restricted in the
diet5,6
• Primary FA in soybean oil
(linoleic acid) and fish oil (EPA
and DHA)1
• Include EFAs (linoleic and -
linolenic acid)1
• Important for cell membrane
structure and function7
• Primary FA that is oxidized8
• Should be restricted in the
diet5,6
• Include oleic acid, the primary
FA in olive oil1
• Olive oil is associated with
favorable effects on risk factors
for CV disease9,10
• Require supplementation with
a source of EFAs1
• Should be a predominant FA in
the diet (~50% of FA intake)5,6

SFA, saturated fatty acid; PUFA, polyunsaturated fatty acid; MUFA, monounsaturated fatty acid; CV, cardiovascular;
FA, fatty acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid.
1. Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):1171-1184. 6. World Health Organization. Diet, Nutrition and the Prevention of
2. Hu FB, et al. J Am Coll Nutr. 2001;20(1):5-19 Chronic Disease. 2002. WHO Technical Report Series 916.
3. Zaloga GP, et al. Clin Nutr Suppl. 2008;3(suppl 1):219 7. Calder PC. Braz J Med Biol Res. 2003;36(4):433-446.
[abstract LB029]. 8. Eritsland J. Am J Clin Nutr. 2000;71(suppl 1):197S-201S.
4. Staiger K, et al. Diabetes. 2006;55(11):3121-3126. 9. Ruiz-Gutiérrez V, et al. J Nutr Biochem. 1997;8:689-695.
12 5. Kris-Etherton PM. J Nutr. 1999;129(12):2280-2284. 10. López-Miranda J, et al. Nutr Rev. 2006;64(suppl 1):S2-S12.
 FATTY ACID CLASSIFICATION:
OMEGA NOMENCLATURE
 The nomenclature refers to the distance, in carbons, of the first
double bond from the  (non-carboxylic acid) end of the carbon chain

-Linolenic acid: -3

 -3: first double bond is
 end
3 carbons from the  end

Linoleic acid: -6

 -6: first double bond is
 end
6 carbons from the  end

Oleic acid: -9

 -9: first double bond is
 end
9 carbons from the  end

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Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):1171-1184.
 FATTY ACID CLASSIFICATION:
OMEGA NOMENCLATURE

-3 -6 -9

• Primary PUFA in fish oil
(EPA, DHA) and plant oil
(-linolenic acid)1
• Dose-dependent anti-
inflammatory2,3 and cellular
immunosuppressive4,5
effects
• Target for oxidation
(multiple double bonds)6
• Primary PUFA in soybean
oil (linoleic acid)1
• Pro-inflammatory4,7 and
immunosuppressive4,7,8
effects
• Target for oxidation
(multiple double bonds)6
• Primary MUFA in olive oil
(oleic acid)1
• Support normal intrinsic
host immune and
inflammatory responses9-11
• Less prone to oxidation
(single double bond)6

PUFA, polyunsaturated fatty acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; MUFA, monounsaturated
fatty acid.

1. Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):1171-1184. 7. Furukawa K, et al. Nutrition. 2002;18(3):235-240.
2. Calder PC. Braz J Med Biol Res. 2003;36(4):433-446. 8. Battistella FD, et al. J Trauma. 1997;43(1):52-58.
3. Hayashi N, et al. JPEN. 1998;22(6):363-367. 9. Granato D, et al. JPEN. 2000;24(2):113-118.
4. Waitzberg DL, et al. JPEN. 2006;30(4): 351-367. 10. Buenestado A, et al. JPEN. 2006;30(4):286-296.
5. Grimm H, et al. JPEN. 1994;18(5):417-421. 11. Cury-Boaventura MF, et al. Life Sci. 2006;78(13):1448-1456.
14 6. Eritsland J. Am J Clin Nutr. 2000;71(suppl 1):197S-201S.
 FATTY ACID CLASSIFICATION:
CHAIN LENGTH1,2

 Long-chain FAs (forming long-chain triglycerides [LCTs])

– FAs ≥14 carbons long
 Medium-chain FAs (forming medium-chain triglycerides
[MCTs])
– FAs 6 to 12 carbons long
 Short-chain FAs
– FAs 2 to 4 carbons long
– Not used in parenteral nutrition

1. Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):1171-1184.

15 2. Waitzberg DL, et al. JPEN. 2006;30(4):351-367.
 PARENTERAL LIPIDS: BEYOND
SOYBEAN OIL

Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):1171-1184.

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 DEVELOPMENTAL EVOLUTION OF
PARENTERAL LIPID EMULSIONS

Evolution of Parenteral Lipid Emulsions

LCT-based (PUFA-rich) Reduce LCT (-6) Introduce -3 and/or -9

Introduce MCT (Reduce -6 and SFA)
• Soybean oil–based • Physical MCT/LCT • Supplemental emulsion
emulsion mixture (soybean and (pure fish oil)
• Safflower oil–based coconut oils) • Emulsions incorporating
emulsion • Structured MCT/LCT olive oil (eg, olive/soybean
emulsion oil emulsion) and fish oil (ie,
fish oil–containing mixed
formulas)

LCT, long-chain triglycerides; PUFA, polyunsaturated fatty acid; MCT, medium-chain triglycerides; FAs, fatty acids.

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 FATTY ACID COMPOSITION OF COMMERCIAL
PARENTERAL LIPID EMULSIONS
LCT-based Reduce LCT (-6) Introduce -3 and/or -9
(PUFA-rich) Introduce MCT (Reduce -6 and SFA)

Intralipid® Lipofundin® Structolipid® Omegaven® ClinOleic® Lipoplus® SMOFlipid®

20%1 MCT-LCT 20%1 20%1 10%1 20%1 20%2 20%1

Oil source 100% soy 50% coconut 36% coconut 100% fish 80% olive 50% coconut 30% soy
50% soy 64% soy 20% soy 40% soy 30% coconut
10% fish 25% olive
15% fish

SFA (%) 15.0 59.4 46.3 21.2 14.5 58.0 40.6

MUFA (%) 24.0 11.0 14.0 24.3 63.7 11.5 29.3

PUFA (%) 61.1 33.8 40.0 42.3 22.0 26.8 26.4

-3 (%) 8.0 4.5 5.0 35.2 2.8 5.4 7.3

-6 (%) 53.1 29.3 35.0 7.1 19.2 21.5 19.1

-9 (%) 24.0 11.0 14.0 15.1 62.3 10.6 27.7

LCT, long-chain triglycerides; MCT, medium-chain triglycerides; SFA, saturated fatty acid; MUFA, monounsaturated fatty
acid; PUFA, polyunsaturated fatty acid.

1. Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):1171-1184.

18 2. Driscoll DF. Nutr Clin Pract. 2006;21(4):381-386.
 IMMUNOSUPPRESSION
AND INFLAMMATION

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 THE HOST INFLAMMATORY
HYPERINFLAMMATION RESPONSE

Healthy
Hyper
Hypo-1
Hypo-2
HYPOINFLAMMATION

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Days

Graph represents a hypothetical situation based on information provided in the references below.
1. Bozza FA, et al. Crit Care. 2007;11(2):R49. 2. Calder PC. Br J Nutr. 2007;98 Suppl 1:S133-S139.

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 FATTY ACIDS AND EICOSANOID PRODUCTION:
-3/W-6 PUFAS AND -9 MUFA
 -3 PUFAs may compete with -6 PUFAs for the same enzymes for
metabolism (provided there is enzyme saturation). When -3 metabolism is
favored, less potent pro-inflammatory eicosanoids are produced
-6 Linoleic acid Pro-inflammatory eicosanoids
2-series prostaglandins
2-series thromboxanes
AA
4-series leukotrienes
Cyclooxygenase
-9 Oleic acid X and 5-lipoxygenase
enzymes
Less potent pro-inflammatory
EPA eicosanoids
3-series prostaglandins
3-series thromboxanes
-3 -Linolenic acid 5-series leukotrienes
21 PUFA, polyunsaturated fatty acid; AA, arachidonic acid; EPA, eicosapentaenoic acid.
Figure created using information obtained from Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):1171-1184.
 -6 PUFAs: IMMUNOSUPPRESSIVE EFFECTS

 In vitro and in vivo impairment of

– Neutrophil chemotaxis and phagocytosis1,2
– Lymphocyte proliferation and reactivity3,4
– Natural killer (NK) and lymphokine-activated killer cell activities5-7
– Monocyte chemotaxis and proliferation6,8
 Administration of -6 PUFAs has been associated with
prolonged graft survival in animal transplant models9,10
 All of these effects are dosage dependent

1. English D, et al. J Pediatr. 1981;99(6):913-916.
2. Wiernik A, et al. Am J Clin Nutr. 1983;37(2):256-261.
3. Francis CM, Shenton BK. Aust NZ J Surg. 1987;57(5):323-329.
4. Sedman PC, et al. JPEN. 1990;14(1):12-17.
22 5. Monson JRT, et al. Eur J Surg Oncol. 1988;14(5):935-943.
6. Loo LS, et al. J Infect Dis. 1982;146(1):64-70.
7. Sedman PC, et al. Br J Surg. 1991:78(11):1396-1399.
8. Fraser I, et al. Clin Nutr. 1983;2(1):37-40.
9. Grimm H, et al. Transpl Immunol. 1995;3(1):62-67.
10. Mertin J, Hunt R. Proc Natl Acad Sci USA. 1976;73(3):928-931.
 -3 PUFAs AND IMMUNE FUNCTION
 Data suggest that an excess of -3 PUFAs may be
immunosuppressive1,2
– In vitro studies demonstrated that DHA and EPA suppress the
proliferation of mitogen- and antigen-stimulated T-cells3
– Parenteral -3 PUFAs have been shown to prolong graft survival in
animal transplant models2
– Fish oil has also been shown to attenuate autoimmune diseases in both
animal models and humans4-7
– Because of these potential immunosuppressive effects, -3 PUFAs
should be used with caution in patients with baseline
immunocompromise8
 The absolute amounts—and, perhaps, the ratio—of -6 to -3 may
be important in determining the extent of immunosuppression2

1. Waitzberg DL, et al. JPEN. 2006;30(4):351-367. 5. Bittiner SB, et al. Lancet. 1988;1(8582):378-380.
2. Grimm H, et al. JPEN. 1994;18(5):417-421. 6. Bates D, et al. J Neurol Neurosurg Psychiatry. 1989;52(1):18-22.
23 3. Søyland E, et al. Eur J Clin Invest. 1993;23(2):112-121. 7. Robinson DR, et al. Arthritis Rheum. 1986;29(4):539-546.
4. Kremer JM, et al. Ann Intern Med. 1987;106(4):497-503. 8. Calder PC. Clin Nutr. 1994;13(2):69-74.
 -9 MUFAs SUPPORT INTRINSIC
HOST IMMUNE RESPONSE
 Limited to no impact on lymphocyte proliferation or NK
cell activity in vitro or ex vivo, in contrast to the inhibitory
effects of linoleic acid1,2
– In healthy volunteers (N = 20), demonstrated low toxicity to
lymphocytes, most likely due to necrosis3
– However, a previous in vitro study4 demonstrated reduced
necrosis of human lymphocytes exposed to -9 oleic acid versus
-6 linoleic acid
 Limited to no impact on neutrophil responses in vitro and
in vivo, in contrast to soybean oil and MCT3,5,6

1. Granato D, et al. JPEN. 2000;24(2):113-118. 4. Cury-Boaventura MF, et al. Life Sci. 2006;78(13):1448-1456.
2. Yaqoob P, et al. Am J Clin Nutr. 1998. 67:129-135. 5. Buenestado, et al. JPEN. 2006;30(4):286-296.
24 3. Cury-Boaventura MF, et al. JPEN. 2008;32(1):81-87. 6. Wanten G, et al. J Lipid Res. 2002;43(4):550-556.
 WHAT SORT OF LIPID EMULSION
HYPERINFLAMMATION WOULD YOU PRESCRIBE?

HIGH -3

Healthy
HIGH -9;
MCT/LCT or -6 Hyper
Hypo-1
Hypo-2
HYPOINFLAMMATION

HIGH -9

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Days

MCT, medium-chain triglyceride; LCT, long-chain triglyceride.

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1. Bozza FA, et al. Crit Care. 2007;11(2):R49. 2. Calder PC. Br J Nutr. 2007;98 Suppl 1:S133-S139.
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 CONCLUSIONS
 PN is indicated when patients cannot receive sufficient nourishment
via oral or enteral routes
 Parenteral lipid emulsions are an essential source of energy, EFAs,
and other important nutrients (eg, lipid-soluble vitamins) and thus
play an important role in healing and recovery
 The FA profiles and biological/clinical activity of the available lipid
emulsions vary greatly
– Therefore, each lipid emulsion has its own unique effects on
biology and physiology
 The appropriate choice of lipid emulsion may mitigate some of the
clinical conditions commonly encountered by patients receiving PN
 The prescription of a parenteral lipid emulsion should be undertaken
with the same care and consideration as any other clinical decision

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