Lipids for intravenous nutrition: a multiple choice question

Philip C. Calder Lipids for intravenous nutrition: a multiple choice question

Philip C. Calder Professor of Nutritional Immunology University of Southampton Fatty acids of importance in intravenous nutrition

Caprylic acid 8:0 Capric acid 10:0 Medium chain Myristic acid 14:0 Palmitic acid 16:0 Oleic acid 18:1ω-9 Linoleic acid 18:2ω-6 Long chain α-Linolenic acid 18:3ω-3 Eicosapentaenoic acid 20:5ω-3 Docosahexaenoic acid 22:6ω-3 Very long chain

Sources of fatty acids of importance in intravenous nutrition

Caprylic acid 8:0 Capric acid 10:0 Coconut oil Myristic acid 14:0 Palmitic acid 16:0 Oleic acid 18:1ω-9 Olive oil ω Linoleic acid 18:2 -6 Vegetable seed oils α-Linolenic acid 18:3ω-3 e.g. Soybean oil Eicosapentaenoic acid 20:5ω-3 Docosahexaenoic acid 22:6ω-3 Fish oil

Fatty acid chain length, and the presence, number, position and configuration (cis versus trans) of double bonds affect physical and physiological properties What should lipids used in artificial nutrition provide?

• Energy • Building blocks • Essential fatty acids

What should lipids used in artificial nutrition provide?

• Energy • Building blocks • Essential fatty acids

• A “good” fatty acid balance • Fatty acids with desirable biological activities (& not fatty acids with undesirable biological activities) Hypothetical timecourse of response to insult

HYPERINFLAMMATION Excess inflammatory eicosanoids, cytokines, reactive oxygen species, adhesion molecules; Hyper POOR

NFκB activation OUTCOME Inflammation IMMUNOSUPPRESSION Hypo Excess immunosuppressive cytokines; Suppressed HLA expression & antigen presentation; Suppressed T cell function INSULT Post-GI surgery patients Standard glucose containing PN with no lipid vs Soybean oil (-7 to +14 d) Some “moderately stressed” and some “severely stressed”

Severely stressed + SO => Worse inflammation with SO

Severely stressed - Lipid

Also reported impaired T cell function with SO A Prospective, Randomized Trial of Intravenous Fat Emulsion Administration in Trauma Victims Requiring Total Parenteral Nutrition

Battistella et al. (1997) The Journal of Trauma: Injury, Infection, and Critical Care 43, 52-60

Polytrauma patients (APACHE II av. 22) Standard glucose containing PN with no lipid vs Soybean oil (10 days)

NK cell activity No lipid Soybean oil 300

250 Length of stay (d) 27 39* 200 P = 0.02 ICU stay (d) 18 29* 150 100

Days on ventilator 15 27* baseline of % 50 Pneumonia (#) 13 22* 0 Total infectious No lipid Soybean oil complications 39 72 INSULT Hypo Hyper

Inflammation reactive oxygenspecies,

HYPERINFLAMMATION Excess inflammatory adhesion molecules; NF eicosanoids, κ B B activation ω cytokines, - 6 PUFAs6

Suppressed T cell T function Suppressed antigen presentation; & HLASuppressed expression Excess immunosuppressivecytokines; IMMUNOSUPPRESSION

OUTCOME POOR

What should lipids used in artificial nutrition provide? • Energy Vegetable oils like • Building blocks soybean oil provide • Essential fatty acids all these things

?But not these

• A “good” fatty acid balance • Fatty acids with desirable biological activities (& not fatty acids with undesirable biological activities)

A view has evolved that there is a need to reduce the linoleic acid “load” in lipid emulsions

⇒Two philosophies: ⇒ Simply dilute the soybean oil with another oil that is fairly inert ⇒ Partially replace soybean oil with another oil or oils that exert benefits in their own right Alternatives to soybean oil?

• Oils containing medium-chain triglycerides (MCTs) i.e. coconut oil

• Olive oil

• Fish oil

• Mixtures of the above Medium chain triglycerides

Medium chain FAs (8:0; 10:0) are: - more soluble than long chain FAs - readily cleared from the circulation - readily used source of calories from fatty acids (not stored) - may be protein sparing (via ketone bodies?) - do not impair liver function - do not impair immune function - do not interfere with pulmonary hydrodynamics or gas exchange - resistant to peroxidation Use of MCT containing lipid emulsions is well established A role for olive oil? Olive oil • Rich in oleic acid (18:1ω-9) • Low in linoleic acid • Contains α-tocopherol and other antioxidants (e.g. polyphenolics) • Generally regarded as healthy (important component of the Mediterranean diet) • Oleic acid is fairly resistant to peroxidation There are now a number of clinical trials of parenteral olive oil (in combination with soybean oil) in HPN and in hospitalised patients

Sala-Vila et al. (2007) Curr. Opin. Clin. Nutr. Metab. Care 10, 165-174 Olive oil in HPN

• Several small studies in adults now published – 3 to 6 months duration • Safe with no adverse effects • Little (?no) different from soybean oil with regard to metabolic, inflammatory, immune or oxidative stress markers

• Soybean oil (n = 10) vs Soybean oil/olive oil (20:80) (n = 11) in patients receiving PN for significant weight loss • 2 weeks • Patients receiving soybean oil/olive oil were less likely to show impaired liver enzymes and elevated triglycerides

• High glucose + Soybean oil/MCT (n = 15) vs Low glucose + Soybean oil/olive oil (20:80) (n = 18) • Severe trauma ICU patients • Low glucose-Soybean oil/olive oil group had lower blood glucose and insulin requirement (!), and shorter duration of mechanical ventilation, fewer infections, better immune function (monocyte HLA-DR expression) and shorter length of ICU stay

But low glucose or olive oil?? • Soybean oil (n = 16) vs Soybean oil/olive oil (20:80) (n = 23) (sequentially in different patients) • Mainly post-surgical ICU patients • > 5 days • No differences in inflammatory markers, infections, ICU stay, hospital stay or mortality • No adverse effects • Soybean oil (n = 49) vs. Soybean oil/olive oil (20:80) (n = 51) • Medical-surgical ICU patients • Mean duration 13 days • No differences in inflammatory markers, infections, ICU stay, hospital stay or mortality • No adverse effects

• Soybean oil/MCT (n = 11) vs Soybean oil/olive oil (20:80) (n = 11) • Severely burned ICU patients • 5-7 days • No differences in inflammatory markers, liver function tests, infections, organ dysfunction, ICU stay, hospital stay or mortality • No adverse effects Olive oil in PN

• Experimental data suggests benefits • Used in several HPN studies – safe • Trialled in medical-surgical ICU, trauma, critically ill and burned patients – safe with no adverse effects • Seems to be little different from Soybean oil in terms of laboratory and clinical outcomes A role for fish oil?

Contains very long chain ω-3 fatty acids (EPA and DHA)

Strong evidence of human health effects: - blood lipids - blood coagulation - inflammation - endothelial function - cardiovascular disease

Antagonise ω-6 fatty acids Hypothetical timecourse of response to insult ω-3 PUFAs HYPERINFLAMMATION Excess inflammatory eicosanoids, cytokines, reactive oxygen species, adhesion molecules; Hyper POOR

NFκB activation OUTCOME Inflammation IMMUNOSUPPRESSION Hypo Excess immunosuppressive cytokines; Suppressed HLA expression & antigen presentation; Suppressed T cell function INSULT Fish oil in PN • A number of studies in post GI-surgery patients • Safe with no adverse effects • Findings are generally consistent: – Less inflammation – Improved immune function – Shorter ICU stay – Shorter hospital stay • One study indicates perioperative may be superior to post-operative • But many of these studies were done in a setting of long hospital stay

Infections Length of ICU stay Length of hospital stay Fish oil in PN in the critically ill Crit. Care Med (2006) 34, 972-979

661 patients receiving TPN for > 3 d: ICU and hospital LOS; antibiotic demand vs. fish oil dose Survival according to fish oil dose Survival vs. Predicted survival

FAVOURS FISH OIL • Severe acute pancreatitis • Soybean oil vs Soybean oil/fish oil • 5 days • Better gas exchange and less requirement for continuous renal replacement therapy • Septic ICU patients • Continuous TPN • Soybean oil/MCT (50:50) vs Soybean oil/MCT/fish oil (50:40:10) • 5 days (Within 24 h of admission to ICU until day 6) • Small study (n =23 in total) • Better gas exchange at d6 in patients receiving fish oil • Less inflammation at d6 in patients receiving fish oil Length of hospital stay shorter in patients receiving fish oil

80 P = 0.038

60

40

LOS (days) 20

0 Soybean/MCT Soybean/MCT/Fish Summary of trials of intravenous fish oil in critically ill patients

Findings are not consistent but there is some evidence for: • Decreased inflammation • Better gas exchange • Decreased length of ICU stay • Decreased length of hospital stay Fish oil in PN - Summary

• Experimental data suggests benefits • Trialled in post-surgical and critically ill patients – safe with no adverse effects • Seems to offer clinical benefit over soybean oil or soybean oil/MCT under the conditions in which the trials have been done • There is a need for bigger and better trials in suitable patient groups If fish oil is good and olive oil might be good, then … … why not put olive oil and fish oil together?? Soybean oil/MCT/olive oil/fish oil

Multicenter study:

249 patients after major abdominal or 25 LOS (days) thoracic surgery

Postoperative length of stay tended to 20 be lower (-2 d) in patients receiving soybean oil/MCT/olive oil/fish oil vs * soybean oil 15 Mertes et al. (2006) Ann. Nutr. Metab. 50, 253-259 10

Subgroup analysis (33 patients): 5 Postoperative length of stay was significantly lower (-7 d) in patients 0 receiving soybean oil/MCT/olive oil/fish Soybean oil Soybean/MCT/ oil vs soybean oil olive/fish Grimm et al. (2006) Eur. J. Nutr. 45, 55- 60 What about fish oil versus olive oil?

or • Post-operative patients in ICU • Soybean/olive oil (20:80) (n = 22) vs soybean/MCT/olive/fish oil (n = 22) • 5 days • Open boxes: Soybean/olive Grey boxes: Fish oil • Liver function better preserved in the group receiving fish oil • Soybean oil/olive oil (n = 14) vs Soybean oil/olive oil + fish oil (n = 13) • Post GI surgery patients • > 5 days • No differences in inflammatory markers, liver function tests, ICU stay, hospital stay or mortality • Significantly lower infection rate with fish oil (23% vs 79%; p = 0.007) • No adverse effects

Summary

• Lipids traditionally used in intravenous nutrition are based on ω- 6 PUFA rich vegetable oils (e.g. soybean oil) • There are indications that use of high ω-6 PUFAs may not be optimal • Alternatives include MCTs, olive oil and fish oil in various combinations with soybean oil • MCTs, olive oil and fish oil all appear well tolerated and without adverse effects • MCTs provide a good energy source and do not impair physiological functions – available for > 15 years; used widely • Olive oil does not impair physiological functions and may (?) offer some immune benefits -> little evidence of real clinical benefit so far • Fish oil modifies inflammation and may offer immune benefits – emerging evidence of clinical benefit Conclusions • Alternatives to pure soybean oil exist already • There is a rationale for using MCTs, olive oil or fish oil to partly replace soybean oil • No serious adverse effects of using these alternatives have been reported • MCTs, olive oil and fish oil may offer clinical benefits compared with soybean oil alone • MCTs are already widely used • Evidence for clinical benefit from fish oil is emerging • Combinations of oils might be useful because they may offer complementary benefits Lipid Emulsions: a Multiple Choice Question

Yes, but with more than one answer!! Alternative lipid emulsions that are currently available

• Lipofundin: 50:50 mixture of coconut oil (MCTs) and soybean oil • Structolipid: Interesterified coconut and soybean oils (50:50) • ClinOleic: 80:20 mixture of olive and soybean oils • Lipidem (aka Lipoplus): 50:40:10 mixture of coconut, soybean and fish oils • SMOFLipid: 30:30:25:15 mixture of coconut, soybean, olive and fish oils • Omegaven: 100% fish oil – should be diluted with another lipid emulsion