Symposium 4. Hot Topics in Parenteral Nutrition. Supported by an unrestricted educational grant from Baxter

Transcription

1 Symposium 4 Hot Topics in Parenteral Nutrition Supported by an unrestricted educational grant from Baxter

2 Rationale for using new lipid emulsions a review of evidence from clinical trials Philip Calder Professor of Nutritional Immunology University of Southampton

3 Will cover: Fatty acid structure & naming Roles of fatty acids Soybean oil in PN (Briefly) Alternatives to soybean oil rationale & reality (exclude paediatric studies) MCT Olive oil Fish oil

4 Fatty acid structure Fatty acids are based upon a recurring structure H C H

5 Generic fatty acid structure H H Methyl terminus H C ( C )n C H H OH O Hydrocarbon chain of varying length Carboxylic acid - Often esterified

6 Generic fatty acid structure H3C COOH VARYING CHAIN LENGTH

7 The fatty acid chain may include double bonds No double bonds: saturated Double bonds: Unsaturated One double bond: Monounsaturated Two or more double bonds: Polyunsaturated (Polyunsaturated fatty acid = PUFA)

8 Complex structures that require a careful (precise) system of naming

9 Fatty acid nomenclature H3C COOH 9 H3C COOH 18:0 Stearic acid 18:1ω-9 Oleic acid 18:2ω-6 Linoleic acid 18:3ω-3 α-linolenic acid H3C 6 H3C 3 COOH COOH

10 Fatty acid chain length, and the presence, number, position and conformation of double bonds affect physical and physiological properties

11 Fatty acids of importance in artificial nutrition Caprylic acid Capric acid Myristic acid Palmitic acid Oleic acid Linoleic acid α-linolenic acid Eicosapentaenoic acid Docosahexaenoic acid 8:0 10:0 Medium chain 14:0 16:0 18:1ω-9 18:2ω-6 Long chain 18:3ω-3 20:5ω-3 Very long chain 22:6ω-3

12 Sources of fatty acids of importance in artificial nutrition Caprylic acid Capric acid Myristic acid Palmitic acid Oleic acid Linoleic acid α-linolenic acid Eicosapentaenoic acid Docosahexaenoic acid 8:0 10:0 Coconut oil 14:0 16:0 18:1ω-9 Olive oil 18:2ω-6 18:3ω-3 Vegetable oils 20:5ω-3 22:6ω-3 Fish oil

13 1. Linoleic acid and α-linolenic acids are the simplest ω-6 and ω-3 PUFAs, respectively 1. Linoleic and α-linolenic acids are ESSENTIAL fatty acids 1. Plant seeds and nuts and oils from these (e.g. sunflower oil, corn oil, soybean oil) tend to be rich in PUFAs, especially in the ω-6 fatty acid, linoleic acid

14 Fatty acids are normally found in esterified form In triglycerides: Food Adipose tissue Blood (lipoproteins) Tissues (e.g. liver; muscle) Emulsions for use in PN In phospholipids: Food Blood (lipoproteins) Cell membranes In cholesteryl esters: Blood (lipoproteins)

15 What should a lipid emulsion provide? Energy Building blocks Essential fatty acids A good fatty acid balance Fatty acids with desirable biological activities

16 Soybean oil was the lipid tradionally used in PN (from early 1960s) so-called MCTs introduced later (mid-1980s) Soybean oil and soybean oil/mct (50:50) are the most widely used lipids in PN

17 The fatty acid composition of soybean oil Fatty acid Palmitic acid (16:0) Stearic acid (18:0) Oleic acid (18:1ω-9) Linoleic acid (18:2ω-6) α-linolenic acid (18:3ω-3) % of total

18 Soybean oil provides energy, essential fatty acids, and fatty acids for building blocks, but.. Excessive supply of ω-6 PUFA Increased 18:2ω-6 and 20:4ω-6 in cell membranes Altered membrane structure Increased eicosanoid production Increased inflammation Decreased cell-mediated immunity

19 Effect of Intralipid on proliferation of rat and human lymphocytes Rat Thymidine incorporation (% of control) 100 Human * * 50 * * 0 * * * Concentration (% v/v) Calder et al. (1994) Clin Nutr 13: 69-74

20 Battistella et al. (1997) J. Trauma 43, Polytrauma patients (APACHE II av. 22) Standard glucose containing TPN with no lipid vs. Intralipid (10 days) No lipid NK cell activity Intralipid * 29* 27* 22* 250 % of baseline Length of stay (d) ICU stay (d) Days on ventilator Pneumonia (#) Total infectious complications P = 0.02 No lipid Lipid

21 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

22 Alternatives to soybean oil? Oils containing medium-chain triglycerides (MCTs) Olive oil Fish oil Mixtures of the above

23 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 Lipoplus (aka Lipidem): 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 at point of use with another lipid emulsion

24 Medium chain triglycerides Medium chain FA (8:0; 10:0) are: - more soluble than long chain FA - 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

25 Soybean oil vs. MCT/soybean oil - Critically ill patients - Soybean oil vs. 50:50 MCT/Soybean oil (10 days) - No difference in % T, CD4, CD8 or NK cells in bloodstream - CD4/CD8 ratio: Soybean oil group declined from 2.11 to 1.70* MCT/soybean oil group 1.93 to 1.89 (implies MCT prevents decline in CD4/CD8 ratio) Gogos et al. (1990) Am. J. Clin. Nutr. 51,

26 Soybean oil vs. MCT/soybean oil Surgery for gastrointestinal cancer Soybean oil vs. MCT/Soybean oil mix (7 days) No difference in lymphocyte proliferation No difference in IL-2 production MCT/soybean oil increased NK cell activity Before After NK cell activity * Soybean oil MCT/Soybean Sedman et al. (1991) Brit. J. Surg. 78,

27 Use of MCT containing lipid emulsions is well established

28 A role for olive oil?

29 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

30 ClinOleic ClinOleic is an 80% olive oil, 20% soybean oil mixture

31 ClinOleic did not affect proliferation of human lymphocytes in vitro Thymidine incorporation (% of control) ClinOleic * Intralipid 40 Ivelip * * Concentration (% v/v) Granato et al. (1996) Nutr Clin Metabol 10: 49S-52S

32 ClinOleic improved host defence in infected rats Bacteremia culture rate (%) Following intravenous E. coli exposure, bacteremia culture rates in lungs and blood were lower in rats treated with ClinOleic (n = 12) versus rats treated with soybean oil (n = 13) or soybean oil/mct (n = 11) emulsions Soybean oil Soybean oil/mct ClinOleic 40 Lung Blood Garnacho-Montero et al. (2002) Nutrition 18,

33 There are now several published clinical trials of ClinOlec in HPN and in burns and critically ill patients Sala-Vila et al. (2007) Curr. Opin. Clin. Nutr. Metab. Care 10,

34 Small study (n = 13) 6 months Previously on soybean oil; reverted back to soybean oil after 6 months ClinOleic Clinical data and events appeared little different from when soybean oil was used, but no statistical analysis No adverse effects

35 Small study (n = 14) 3 months No effect on inflammatory or immune outcomes No effect on oxidative stress No adverse effects

36 Small study (n = 6 vs. n = 4 Soybean oil) 3 months No adverse effects

37 Controlled trial of ClinOleic (n = 21) vs. soybean oil (n = 20) 5 weeks Few differences between groups No difference in inflammatory or oxidative stress No adverse effects

38 High glucose + Soybean oil/mct (n = 15) vs. Low glucose + ClinOleic (n = 18) Severe trauma ICU patients Low glucose-clinoleic 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 ClinOleic??

39 Soybean oil (n = 16) vs. ClinOleic (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

40 Soybean oil/mct (n = 11) vs. ClinOleic (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

41 ClinOleic Experimental data suggests many benefits Used in several HPN studies safe Trialled in trauma, critically ill and burned patients one study in each no adverse effects More (& bigger) clinical trials are needed

42 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

43 ω-3 fatty acids and inflammatory mediators ω-3 fatty acids are incorporated into inflammatory cell membranes in place of ω-6 arachidonic acid ω-3 fatty acids decrease production of inflammatory eicosanoids from arachidonic acid (e.g. PGE2, LTB4) ω-3 fatty acids decrease production of inflammatory cytokines (TNF, IL-1 and IL-6) by monocytes/ macrophages mechanism via reduced gene expression

44 Increased long chain ω-3 fatty acid supply Altered fatty acid composition of cell membranes (more EPA and DHA; less arachidonic acid) Improved cell function Improved clinical outcome

45 Three lipid emulsions containing fish oil are currently available Lipoplus (aka Lipidem): 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 at point of use with another lipid emulsion

46 Parenteral nutrition involving fish oil alters eicosanoid balance 40 Ratio of LTB4/LTB5 Received Soybean oil/mct (50:50) or Soybean oil/mct/fish oil (50:30:20; prototype Lipoplus ) from d1 post-op to d6 post-op + ω-3 PUFA Control Patients undergoing intestinal surgery Pre-op Day 6 Day 10 Post-op Wachtler et al. (1997) J. Trauma 42,

47 . and cytokine production * TNF- aα (%) Pre-op Post-op Day 6 Day 10 Soybean/MCT Soybean/MCT/fish Wachtler et al. (1997) J. Trauma 42,

48 Post-surgery Lipid free TPN vs. 10% soybean oil vs. 8.3% soybean + 1.7% fish oil (Omegaven) 5 days No differences in blood lymphocyte, T cell, CD4, CD8, B cell or NK cell numbers No differences in lymphocyte proliferation IL-2 production increased in fish oil group Suggestive of Post-surgery decline in IFN-γ prevented in improved immunity fish oil group

49 Surgical patients Soybean oil vs. fish oil (Omegaven) Day -1 and days +1 to +5 TNF-α production by whole blood decreased at d +5 in the fish oil group Serum IL-6 lower in the fish oil group at d 0, +1 and +3 Monocyte expression of HLA-DR increased in the fish oil group at d +3 and +5 No differences in infection rate or mortality ICU (4.1 vs. 9.1 d) and hospital stay (17.8 vs d) shorter in the fish oil group Serum IL-6 (pg/ml) * * 0 * 1 3 HLA-DR +ve monocytes (%) * * 5

50 (2007) 35, Abdominal surgical patients from 4 units (n = 256) Soybean oil vs. Soybean oil/mct/ Fish oil (50:40:10) (Lipoplus) 5 days No difference in postoperative complications Length of hospital stay (days) P = SO MCT/SO/FO

51 Soybean oil/mct (50:50) post-op vs. Soybean oil/mct/fish oil (50:40:10) post-op vs. Soybean oil/mct/fish oil (50:40:10) 2-3 d pre-op & post-op Soybean/MCT % ventilated % wound infected Days ICU LOS (d) % readmission ICU % mortality Soybean/MCT/fish Post-op Post-op Pre & Post-op * 12 17* * 5* 3**

52 Surgical patients Soybean oil vs. Soybean oil/mct/olive oil/fish oil (SMOFLipid) 6 days Altered eicosanoid balance 25 LOS (days) 20 * Soybean oil Soybean/MCT/ olive/fish

53 Clinical trials of lipid emulsions including fish oil in post-gi surgical patients show Altered eicosanoid balances Decreased inflammatory cytokines Decreased length of ICU stay (1 study) Decreased length of hospital stay (4 studies) Perioperative may be superior to post-operative

54 Eur. J. Clin. Nutr. (2008) 62, ICU patients after aorta aneurysm surgery Soybean oil/mct vs. Soybean oil/mct/fish oil (50:40:10) (Lipoplus) No effect on glucose metabolism or inflammatory markers No significant effects on clinical outcomes, but a trend for decreased ICU and hospital length of stay

55 Studies in critical illness

56 Am. J. Respir. Crit. Care Med. (2003) 167, Septic patients in ICU Intolerant of enteral nutrition Soybean oil vs. Fish oil (Omegaven) 5 days Production of TNF-α, IL-1β, IL-6 and IL-8 by mononuclear cells stimulated with endotoxin measured Soybean oil Fish oil TNF-α IL1-β IL Day IL Day

57 Mayer et al. (2003) Intensive Care Med. 29, Septic patients in ICU Intolerant of enteral nutrition Soybean oil vs. Fish oil (Omegaven) 10 days White cell count and serum CRP tended to be lower at d3 and d7 LTB5 production by leukocytes higher at d3, d7, d10 TXA3 production by platelets higher at d3, d7, d10 Neutrophil responses normalised at d7

58 Medical ICU patients Soybean oil/mct vs. Soybean oil/mct/fish oil (Omegaven) 7 days No differences in inflammatory or immune markers, bleeding, ventilation requirement, infections, length of ICU stay or mortality

59 Crit. Care Med (2006) 34, Prospective open-label, multicenter study; Omegaven 661 patients receiving TPN for > 3 d: ICU and hospital LOS; antibiotic demand vs. fish oil dose

60 Survival according to fish oil dose

61 Survival vs. Predicted survival

62 Severe acute pancreatitis Soybean oil vs. Soybean oil/fish oil (Omegaven) 5 days No differences in inflammatory outcomes, infections, length of ICU stay or length of hospital stay Better gas exchange and less requirement for continuous renal replacement therapy

63 Results from clinical trials of lipid emulsions including fish oil in critically ill patients are inconsistent but some trials show: Altered eicosanoid balances Decreased inflammatory cytokines Decreased infections (antibiotic demand) Decreased length of stay Improved survival

64 Summary & conclusions Lipids traditionally used in artificial nutrition are based on ω-6 PUFA rich vegetable oils (e.g. soybean oil) There are indications that use of high ω-6 PUFA may not be optimal Alternatives include MCT, olive oil and fish oil either alone or in various combinations with soybean oil MCT containing emulsions are well established but the others, although available for use, are still being trialled Emulsions that contain olive oil or fish oil are well tolerated and without adverse effects Fish oil modifies inflammation and may offer immune benefits Parenteral supply of ω-3 fatty acids appears to be beneficial in surgical patients perioperative may be better than postoperative Parenteral supply of ω-3 fatty acids has been trialled in septic patients there may be clinical benefit, but more trials are needed

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66 Current evidence and ongoing trials on the use of glutamine in critically ill and surgical patients Alison Avenell Health Services Research Unit University of Aberdeen HSRU is funded by the Chief Scientist Office of the Scottish Government Health Directorates. The author accepts full responsibility for this talk.

67 Glutamine (1) Most numerous amino acid in the body (60% of free amino acids in muscle) Carrier for inter-organ nitrogen Preferred fuel for enterocytes, hepatocytes, lymphocytes and macrophages Nitrogen donor for nucleotides and amino sugars Substrate for renal ammonia genesis Precursor of glutathione, taurine, arginine Health Services Research Unit

68 Glutamine (2) Usually considered non-essential amino acid Plasma levels fall in catabolic illness Not usually present in parenteral nutrition products Supplementation improves nitrogen balance May reduce bacterial translocation across the gut wall Improved glycaemic control Increased expression of heat shock protein Health Services Research Unit

69 Data handling for review Searched until August 2008 (5 databases and 4 journals) Outcomes from last available time point Intention to treat analysis using all people randomised Random effects (conservative analysis) Assumed standard deviations where missing Presumed PN regimes isonitrogenous and isocaloric Health Services Research Unit

70 Mortality - TPN in critical illness RR 0.71 (95%CI 0.49 to 1.03) Health Services Research Unit

71 Mortality - EN in critical illness RR 1.05 (95% CI 0.71 to 1.54) Health Services Research Unit

72 Mortality - TPN in mixed hospital population RR 0.72 (95% CI 0.39 to 1.32) Health Services Research Unit

73 Infection - TPN in critical illness RR 0.78 (95% CI 0.63 to 0.97) Health Services Research Unit

74 Infection - EN in critical illness RR 0.91 (95% CI 0.74 to 1.10) Health Services Research Unit

75 Infection - TPN in surgery RR 0.43 (95% CI 0.27 to 0.69) Health Services Research Unit

76 Infection funnel plot for publication bias Health Services Research Unit

77 Length of stay - TPN in critical illness WMD 0.09 days (95% CI to 2.02) Health Services Research Unit

78 Length of stay - EN in critical illness WMD days (95% CI to 0.77) Health Services Research Unit

79 Length of stay - TPN surgery WMD days (95% CI to -1.72) Health Services Research Unit

80 Length of stay in critical care WMD 0.02 days (95% CI to 1.16) Health Services Research Unit

81 Organ failure (other than requiring ventilation) Health Services Research Unit

82 Pancreatitis mortality and infections Health Services Research Unit

83 Mortality - dose of glutamine Health Services Research Unit

84 Cochrane reviews Glutamine supplementation for young infants with severe gastrointestinal disease (Grover et al 2007) 2 trials, 100 infants, with no significant effect on infections or mortality Glutamine supplementation to prevent morbidity and mortality in preterm infants (Tubman et al 2007) 7 trials (4 TPN), 2365 infants, with no significant effect on morbidity or mortality Health Services Research Unit

85 Conclusions No evidence to suggest that parenteral or enteral glutamine is harmful Mortality No statistically significant effect Infection Beneficial but risk of bias? Benefit if require TPN in pancreatitis? Good quality RCTs are needed Health Services Research Unit

86 SIGNET trial (Scottish Intensive care Glutamine or selenium Evaluative Trial) Randomised blinded, controlled trial in 500 adult patients requiring TPN in ICU Selenium 500µg/d for 7 days Glutamine 20g/d for 7 days Glutamine and selenium Control Outcomes included infections, mortality, ICU stay, hospital stay, and economic evaluation Health Services Research Unit

87 REDOXs trial Randomised blinded, controlled trial in 1200 ventilated adult patients with severe organ failure, supplementation up to 28 days Selenium 500µg/d IV and enteral antioxidants Glutamine 0.35g/kg/d IV and 30g enteral Glutamine and antioxidants Control Outcomes included infections, mortality, ICU stay, hospital stay, and quality of life Health Services Research Unit

88 Acknowledgements Daren Heyland and his review group Anne Milne, Bernie Croal, Mark Crowther Chief Scientist Office of the Scottish Government Health Directorates Medical Research Council Fresenius Kabi Oxford Nutrition Health Services Research Unit

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