Ashraf El Houfi MD MS (pulmonology) FRCP (UK) EDIC Consultant ICU Dubai Hospital

Ashraf El Houfi MD MS (pulmonology) FRCP (UK) EDIC Consultant ICU Dubai Hospital

Protein Lipids Lipids?

Lipids Energy source/storage 9 Kcal/g Carb.& Prot. 4 Kcal/g Membrane Function glycero-phospholipids Steroid hormones (estrogen, testosterone, cortisol) Fat-soluble vitamins (A, D, E and K)

Lipids Cell Signaling G protein-coupled, sphingosine-1-phosphate, diacylglycerol (DAG), phosphatidylinositol phosphates (PIPs)..

Fatty Acids & Inflammation

Inflammatory Mediators A variety of chemical mediators from inflammatory cells, and injured tissue actively contribute to and adjust the inflammatory response. The released mediators include (1) vasoactive amines histamine & serotonin (2) peptide (e.g., bradykinin), and (3) eicosanoids (Fatty Acid driven) (e.g., Thromboxanes, Leukotrienes, Prostaglandins).

Fatty Acids Short chain (SCFAs) have 2 6 carbons, medium chain (MCFAs) have 6 14 carbons, long chain (LCFAs) have 14 carbons.

Fatty Acids Saturated FAs have no double bonds, Mono-unsaturated FAs (MUFAs) have one double bond, Poly-unsaturated FAs (PUFAs) have two double bonds.

Fatty Acids The location of the first double bond, counting from the methyl end of the molecule, is called the Ʊ (Omega end) carbon methyl end Omega end

Omega end Omega end

Fish oils Cold water fish are rich in eicosapentaenoic acid (EPA) and docosahexonoic acids (DHA) Humans have limited capacity to synthesis DHA and EPA from alpha-linolenic acid (ALA), through desaturase enzymes. During acute illness these desaturases are markedly down-regulated so that EPA and DHA synthesis from ALA is negligible.

Arachidonic Acid ( AA ) (pro-inflammatory fatty acid ) Lipo-oxygenase Cyclo-oxygenase LT A4 LT B4 LT C4 LT D4 LT E4 Pro-inflammatory Eicosanoids ( PG, LT, TX ) PG E2 PG D2 PG G2 PG I2 TX A2

Inflammation Modulating Nutrients Ʊ 3 Eicosa-Penta-enoic Acid (EPA) Docosa-Hexonoic Acids (DHA) Ʊ 3 Displaces AA, in the cell membranes, making less AA available to produce pro-inflammatory mediators Precursor for the eicosanoids (PGE3, TXA3) that are less pro-inflammatory than the eicosanoids derived from arachidonic acid.

Inflammation Modulating Nutrients Ʊ 6 Gamma Linolenic Acid (GLA) Ʊ 6 Precursor for prostaglandin E1, a pulmonary vasodilator, and mediators that are less inflammatory than the pro-inflammatory Eicosanoids produced by Arachidonic Acid

Dietary Modulation of Inflammation Borage Oil GLA DGLA Replacing AA with GLA results in Arachidonic Acid Cyclooxygenase Lipoxygenase X Fish Oil EPA Replacing AA with EPA results in & DHA PGE 1 and eicosanoids that are less inflammatory Decreased proinflammatory eicosanoids (LTB 4, TXA 2, PGE 2 ) Eicosanoids that are less inflammatory (TXA 3, PGE 3, LTB 5 ) E012373A 17

Evidence for fish oil ARDS or ALI effects demonstrated in 3 major RCT duration ventilation ICU and hospital stay new organ failure 2 studies also showed mortality reduction Meta-analysis of 3 trials (n=441) NNT to save an additional life at 28 days 5 Gadek at.al :crit.care.med 1999 1409-1420 Singer Crit Care Med 2006:34;1033 Pontes -Arruda Crit Care Med 2006:34;2345

EPA & GLA Do they work!!! 700 600 500 400 300 200 100 0 EPA + GLA EPA Standard EPA+GLA EPA Standard

EPA & GLA Do they work!!! LTB4 80 70 60 50 40 30 20 10 0 EPA + GLA EPA Standard EPA+GLA EPA STANDARD

RCT of 146 critically ill patients with ALI Double-blinded; ITT 30 25 25 20 15 10 9.6 13.2 11 14.8 15.7 5 0 Vent Days ICU Days ICU Deaths EPA+GLA control Gadek Crit Care Med 1999;27:1409

RCT of 100 critically ill patients with ALI, Single center un-blinded; not ITT 60 50 53 40 30 30 20 12.1 14.7 13.5 15.6 10 0 Vent Days ICU Days ICU Deaths EPA+GLA control Singer Crit Care Med 2006:34;1033

RCT of 165 critically ill patients with ARDS secondary to sepsis, double-blinded; not ITT 50 45 40 35 30 25 20 15 10 5 0 46 31 22.2 23.4 17.2 14.6 Vent Days ICU Days ICU Deaths EPA+GLA control Pontes -Arruda Crit Care Med 2006:34;2345

EPA & GLA Do they work!!! 20 15 10 5 P= 0.011 P= 0.016 16 14 12 20 0 ventilator days EPA &GLA standard ICU Stay Gadek at.al :crit.care.med 1999 1409-1420 Singer Crit Care Med 2006:34;1033 Pontes -Arruda Crit Care Med 2006:34;2345

EPA & GLA Do they work!!! 30 25 20 15 P = 0.015 28% 10 5 0 8 % 4 /51 13 /47 EPA & GLA standard Organ failure Number of New Organ Failure Pontes -Arruda Crit Care Med 2006:34;2345 Singer Crit Care Med 2006:34;1033

Overall Effect on Mortality www.criticalcarenutrition.com

Canadian Clinical Practice Guidelines www.criticalcarenutrition.com

* April 2017 www.criticalcarenutrition.com Canadian Clinical Practice Guidelines www.criticalcarenutrition.com * April 2017 2015 Recommendation: Based on 3 level 1 studies and 5 level 2 studies, the use of an enteral formula with fish oils, borage oils and antioxidants in patients with Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) should be considered. 2015 Discussion: With the addition of 1 new study (Kagan 2015), the committee acknowledged that the lack of a treatment effect of enteral fish oils, borage oils and antioxidants remained. The sparse data on ventilator associated pneumonia i.e. 3 studies showing no effect, was noted. There were concerns about the adequacy of the control group in several studies (i.e. high fat formula, additional protein). Since the delivery of fish oil or fish oil/borage oil/antioxidant components as a bolus could have diminished the treatment effect, a sensitivity analysis with and without the Rice 2011 was done. A significant effect on 28 day mortality was only seen when this study was excluded. The committee agreed that the signals from the Grau-Carmona study, the first large, multicenter trial that used a usual care control solution and had results were negative results still had to be considered and it was agreed to continue with a recommendation for should be considered

Sepsis and omega 3 lipids In animal models, fish oil has shown beneficial effects May increase bacterial killing Improves survival Maintains blood flow to intestine

Surgical patients omega 3 Enteral and partenteral omega 3 Prevention infections Reduced length of hospital stay Pre-op use in cardiac surgery patients - reduction AF post-op, reduction length of hospital stay Good safety profile

Updated systematic review and meta-analysis fish oil lipid emulsions in critically ill patients: William Manzanares, Pascal L Langlois, Rupinder Dhaliwal, Margot Lemieux and Daren K Heyland Critical Care (2015) 19:167

Effects on infections of parenteral fish oil containing emulsions

Effects on mortality of fish oil lipid emulsion strategies

Effects on mechanical ventilation days of parenteral fish oil containing emulsions

Effects on hospital length of stay of parenteral fish oil containing emulsions

Effects on ICU length of stay of parenteral fish oil containing emulsions

Conclusions This updated systematic review & meta-analysis, demonstrates that FO-containing LEs in critically ill patients may be able to reduce the 1. infectious complications (significant) 2. reduction in the duration of MV (Numeric) 3. Hospital/ICU LOS (Numeric)

Canadian Clinical Practice Guidelines www.criticalcarenutrition.com

(A.S.P.E.N.) (SCCM) February 2016 Question: Should EN formulas with fish oils (FOs), borage oil, and antioxidants be used in patients with ALI or ARDS? Answer: We cannot make a recommendation at this time regarding the routine use of an enteral formulation characterized by an anti inflammatory lipid profile (eg, omega-3 FOs, borage oil) and antioxidants in patients with ARDS & severe ALI, given conflicting data. [Quality of Evidence: Low to Very Low]

References 1. Carpentier YA, Dupont IE. Advances in intravenous lipid emulsions. World J Surg. 2000;24 2. Wanten GJ, Calder PC. Immune modulation by parenteral lipid emulsions. Am J Clin Nutr. 2007;85:1171 84. 3. Hecker M, Mayer K. Intravenous lipids in adult intensive care unit patients. World Rev Nutr Diet. 2015;112:120 6. 4. Calder PC, Jensen GL, Koletzko BV, Singer P, Wanten GJA. Lipid emulsions in parenteral nutrition of intensive care patients: current thinking and future directions. Intensive Care Med. 2010;36:735 49. 5. Ren T, Cong L, Wang Y, Tang Y, Tian B, Lin X, et al. Lipid emulsions in parenteral nutrition: current applications and future developments. Expert Opin Drug Deliv. 2013;10:1533 49. 6. Waitzberg DL, Torrinhas RS. Fish oil lipid emulsions and immune response: what clinicians need to know. Nutr Clin Pract. 2009;24:487 99. 7. Edmunds CE, Brody RA, Parrott JS, Stankorb SM, Heyland DK. The effects of different IV fat emulsions on clinical outcomes in critically ill patients. Crit Care Med. 2014;42:1168 77. 8. Pradelli L, Mayer K, Muscaritoli M, Heller AR. n-3 fatty acid enriched parenteral nutrition regimens in elective surgical and ICU patients: a meta-analysis. Crit Care. 2012;16:R184. 9. Palmer AJ, Ho CKM, Ajibola O, Avenell A. The role of n-3 fatty acid supplemented parenteral nutrition in critical illness in adults: a systematic 10. Manzanares W, Dhaliwal R, Jurewitsch B, Stapleton RD, Jeejeebhoy KN, Heyland DK. Parenteral fish oil lipid emulsions in the critically ill: a systematic review and meta-analysis. JPEN J Parenter Enteral Nutr. 2014;38:20 8. 11. Khor BS, Liaw SJ, Shih HC, Wang LS. Randomized, double blind, placebocontrolled trial of fish-oilbased lipid emulsion infusion for treatment of critically ill patients with severe sepsis. Asian J Surg. 2011;34:1 10.