Lipids in TPN: Ready for Prime Time? Dr Jonathan Tan Senior Consultant Anaesthesiology and Intensive Care Tan Tock Seng Hospital, Singapore

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1 Lipids in TPN: Ready for Prime Time? Dr Jonathan Tan Senior Consultant Anaesthesiology and Intensive Care Tan Tock Seng Hospital, Singapore

2 Disclosures Travel and speakers honourarium from Abbott, Baxter, Fresenius, Nestle.

3 Lipids FAT: Necessary EVIL!! Major energy store and source. High energy content and low hydration Essential in cell structure Metabolically active molecules: Inflammation, Cell signalling etc

4 Lipids in TPN High Energy, low volume: avoid energy deficits Avoid Hyplerglycaemia, Hypercarbia Source of essential FFAs Fat soluble vitamins (A,D,E,K, Choline) Typically 20-40% of non protein calories Immuno-Nutrition therapy/modulation?

5 Structure Activity Relationship

6 Fatty Acid Classification: Saturation SFAs PUFAs MUFAs Most FAs in coconut oil 1 Increased risk of CV disease 2 Acute adverse effects include endothelial toxicity, apoptosis, and inflammation 3,4 Should be restricted in the diet 5,6 Primary FA in soybean oil (linoleic acid) and fish oil (EPA and DHA) 1 Include EFAs 1 Important for cell membrane structure and function 7 Primary FA that is oxidized 8 Should be restricted in the diet 5,6 Include oleic acid, the primary FA in olive oil 1 Olive oil is associated with favorable effects on risk factors for CV disease 9,10 Require supplementation with a source of EFAs 1 Should be the predominant FA in the diet (~50% of FA intake) 5,6 SFA, saturated fatty acid; PUFA, polyunsaturated fatty acid; MUFA, monounsaturated fatty acid; FA, fatty acid; CV, cardiovascularepa, eicosapentaenoic acid; DHA, docosahexaenoic acid; EFA, essential fatty acid. 1. Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5): Hu FB, et al. J Am Coll Nutr. 2001;20(1): Zaloga GP, et al. Clin Nutr Suppl. 2008;3(suppl 1):219 [abstract LB029]. 4. Staiger K, et al. Diabetes.2006;55(11): Kris-Etherton PM. J Nutr. 1999;129(12): World Health Organization. Diet, Nutrition and the Prevention of Chronic Disease WHO Technical Report Series Calder PC. Braz J Med Biol Res. 2003;36(4): Eritsland J. Am J Clin Nutr. 2000;71(suppl 1):197S-201S. 9. Ruiz-Gutiérrez V, et al. J Nutr Biochem. 1997;8: López-Miranda J, et al. Nutr Rev. 2006;64(suppl 1):S2-S12.

7 Omega Nomenclature The w nomenclature refers to the distance, in carbons, of the first double bond from the w (non-carboxylic acid) end of the carbon chain w-3: first double bond is 3 carbons from the w end a-linolenic acid: w-3 w end w-6: first double bond is 6 carbons from the w end Linoleic acid: w-6 w end w-9: first double bond is 9 carbons from the w end Oleic acid: w-9 w end Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):

8 Saturated Fatty Acid Classification: ω Nomenclature w-3 w-6 w-9 Primary PUFA in fish oil (EPA and DHA) 1 Dose-dependent antiinflammatory 2,3 and cellular immunosuppressive 4,5 effects Target for oxidation (multiple double bonds) 6 Primary PUFA in soybean oil (linoleic acid) 1 Pro-inflammatory 4,7 and immunosuppressive 4,7,8 effects Target for oxidation (multiple double bonds) 6 Primary MUFA in olive oil (oleic acid) 1 Support normal intrinsic host immune and inflammatory responses 9-11 Less prone to oxidation (single double bond) 6 PUFA, polyunsaturated fatty acid; eicosapentaenoic acid; DHA, docosahexaenoic acid; MUFA, monounsaturated fatty acid. 1. Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5): Calder PC. Braz J Med Biol Res. 2003;36(4): Hayashi N, et al. JPEN J Parenter Enteral Nutr. 1998;22(6): Waitzberg DL, et al. JPEN J Parenter Enteral Nutr. 2006;30(4): Grimm H, et al. JPEN J Parenter Enteral Nutr. 1994;18(5): Eritsland J. Am J ClinNutr. 2000;71(suppl 1):197S-201S. 7. Furukawa K, et al. Nutrition. 2002;18(3): Battistella FD, et al. J Trauma. 1997;43(1): Granato D, et al. JPEN J ParenterEnteralNutr. 2000;24(2): Buenestado A, et al. JPEN J ParenterEnteralNutr. 2006;30(4): Cury-Boaventura MF, et al. Life Sci. 2006;78(13):

10 SIRS CARS response story... Calder, Clin Nutr 2010; 29: 5-12

11 Oxidative Stress Acute respiratory distress syndrome Inadequate wound healing Sepsis Multi-organ failure Shock Trauma Acute Myocardial Infarction Lipid peroxidation: occurs during ischemia or reperfusion

12 Overproduction of ROS: Activated leucocytes, hypoxia or hyperoxia, ionizing radiation Shock, trauma, sepsis Lipid peroxidation Insufficiency or depletion of anti-oxidant systems AOX ROS AOX ROS Oxidative stress OXIDATIVE CELL DAMAGE ORGAN DAMAGE OR FAILURE

Clin Lab. 2007;53(3-4):199-209. 2. Fuhrman B, et al. Nutrition.

13 Nutrition-Related Determinants of Oxidative Stress Reduce Pro-oxidant lipids Anti-oxidant supplementation. 1. Mishra V. Clin Lab. 2007;53(3-4): Fuhrman B, et al. Nutrition. 2006;22(9): Thérond P, et al. CurrOpinClinNutrMetab Care. 2000;3(5):

14 Which Lipid?? Choice of lipid to affect oxidation Choice of lipid to affect immunomodulation

15 w-6 PUFAs Soyabean oil; Linoleic acid; essential FA Main Lipid in TPN, lipid emulsions Oxidative stress Eicosanoid production from w-6 PUFAs more proinflammatory and suppresses cell mediated immune function May worsen clinical outcomes. Heyland et al J Am Med Assoc. 1998;280:

16 Soybean oil provides energy, essential fatty acids and fatty acids for building blocks, but Excessive supply of ω-6 fatty acids Increased 18:2 ω-6 and 20:4 ω-6 in cell membranes Altered membrane structure Increased eicosanoid production Increased inflammation Decreased cell-mediated immunity Calder, Clin Nutr 2010; 29: 5-12

17 Effect of omega-6 fatty acid based lipid emulsions Mayer et al., Curr Opin Clin Nutr Metab Care 2006; 9:

18 w-9 MUFAs and Immune Function Limited to no impact on lymphocyte proliferation or NK cell activity in vitro or ex vivo, in contrast to the inhibitory effects of linoleic acid 1-3 Limited to no impact on neutrophil responses in vitro and in vivo, in contrast to soy oil and MCT 4-6 Based on available data, w-9 MUFAs are generally considered to be immune neutral 1. Granato D, et al. JPEN J Parenter Enteral Nutr. 2000;24(2): Cury-Boaventura MF, et al. Life Sci. 2006;78(13): Yaqoob P, et al. Am J Clin Nutr : Cury-Boaventura MF, et al. JPEN J Parenter Enteral Nutr. 2008;32(1): Buenestado, et al. JPEN J Parenter Enteral Nutr. 2006;30(4): Wanten G, et al. J Lipid Res. 2002;43(4):

19 w-3 PUFAs Modifications of FA profiles of cells & tissues occurs after w-3 PUFA supplementation EPA, DHA incorporated into cells, partly displacing FAs such as arachidonic acid Changed eisosanoid production profile Alters physical properties of cell membranes Modifys transcription factors and gene expression.

20 Modulation of inflammation by omega-6 and omega-3 fatty acids Carlson et al., JPEN 2013;37:15-22

21 w-3 PUFAs Overall less immune suppression, less proinflammatory vs Soybean oils Immunomodulation, leucocyte modification Cytokine reduction Effects appear to be dose dependent.

22 Postulated effects of w-6 and w-3 fatty acids on the inflammatory and immune response Inflammatory tone can be changed by n-3 FA to weakly pro-inflammatory Mayer et al., Curr Opin Clin Nutr Metab Care 2006; 9:

23 w-3 PUFAs in PN Omegaven: Pure fish oil; 3g EPA+DHA/100ml Lipoplus/Lipidem: 50%MCT, 40%Soybean, 10%FishOil; 1.2g EPA+DHA/100ml SMOF Lipid: 30%MCT, 30%Soybean, 25%Olive Oil, 15%FishOil; 1g EPA+DHA/100ml Not used alone; no essential FAs

24 Fish Oils latest Fad or new best thing?

25 w-3 PUFAs: Clinical Studies Heller et al Crit Care Med 2006 Prospective open label trial, infusion of w-3 FA supplement to soybean oil TPN. Dose physician determined Critically ill patients: Major abdominal surgery (incld elective surgery), abdominal sepsis, nonabdominal sespsis, multitrauma, severe TBI, others. Total 661 pts Reduced ICU, Hospital LOS with FO>0.05g/kg/day.

26 w-3 PUFAs: Clinical Studies Chen B et al, JPEN 2010 Meta-analysis of FO enriched PN in elective major abdominal surgery Improved hospital and ICU LOS, improved postop infection rates, improved LFTs No difference in mortality or cardiac complications (Not ICU pts.).

29 hhh

30 Significant shortened hospital LOS in treatment group Few trials with w-3 FA supplemented PN in non elective post op critically ill. Mainly small single centre studies, lost data, inclusion of studies that reported only biochemical and immunological endpoints. Heterogenous patient groups..

31 JPEN epub 22 April No elective patients Relevant clinical outcomes in critially ill Some trials included in previous meta analysis PN FO vs placebo (EN, PN, Both)

32 Mortality Trend toward reduction in mortality. RR 0.71; 95%CI ; p=0.08

33 Ventilator days Trend toward reduced ventilator free days After excluding EN fed trials, WMD, -1.81; 95%CI to 0.36

34 Infection No effect on infection No effect on ICU LOS

36 .

37 Lipoplus: 50%MCT, 40%SO, 10%FO 25-30kcal/kg/day; protein 1.5g/kg/day Commenced asap post randomisation; EN allowed but PN at least 50% x 5Days Large 159 pt study 0.1gFO/kg/day average Heterogenous ICU grp; no specific infection reduced.

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41 . Infection

42 RCTs with clinical outcomes in ICU pts Included the Spanish RCT: large influence PN based signal for mortality lost, but EN based pharmaconutrient strategy showed tendency to reduction in mortality Reduced infections Trend toward reduced MV and Hosp LOS Heterogenous; some small studies; FO dose?.

44 Optimal dose and timing unknown g/kg/day FO most common and appears effective Timing? Most trial started first 24-48hrs post ICU admission Analysis cannot make conclusive, strong definitive recommendations on FO use in critically ill. IV FO demonstrated to be beneficial in subgroup of patients: severe sepsis, sepsis, ARDS Need dose finding studies in correct pt grps.

45 Liver Function Test Abnormal LFTs: Glucose and Lipid load Ensure oxidative metabolism of glucose by liver not exceeded. Not > 5g/min of Glucose Fatty Liver? Cholestasis? Large convincing level 1 evidence in Neonates and Paeds pts that Fish Oil based lipids improves deranged LFTs in TPN Adult literature: few small RCTs with improved LFTs vs Soy, Soy+Olive combo..

46 Guidelines

48 ESPEN Guidelines on Parenteral Nutrition: Intensive Care Singer et al., Clinical Nutrition 2009; 28: Addition of EPA and DHA to lipid emulsions has demonstrable effects on cell membranes and inflammatory processes Fish oil-enriched lipid emulsions probably decrease length of stay in critically ill patients Grade B Grade B

49 Canadian Guidelines 2015 Reduce omega-6 FA/Soybean emulsions Replace with??

50 Which Lipid??

51 Practically? What s available in the larder?? Reduce Soyabean oils Olive oils: Neutral, Safe Enteral FO: not recommended Use a mix of everything? FO: at least 0.1g/kg/day Timing and Patient selection: TBI? Multiple Trauma? Abdominal sepsis? Who s doing the next big study?

52 Thank you

Dr Ahmad Shaltut Othman Anaesthesiologist & Intensivist Hosp Sultanah Bahiyah Alor Setar

FEEDING WITH FISH OIL Dr Ahmad Shaltut Othman Anaesthesiologist & Intensivist Hosp Sultanah Bahiyah Alor Setar New horizons in clinical nutrition from Support to Therapy Landmarks in Parenteral Nutrition