Omega-3 supplementation in patients with sepsis: a systematic review and meta-analysis of randomized trials
Annals of Intensive Care 20177:58, DOI: 10.1186/s13613-017-0282-5©
Clara Lu, Sunjay Sharma, Lauralyn McIntyre, Andrew Rhodes, Laura Evans, Saleh Almenawer, Lori Leduc, Derek C. Angus and Waleed Alhazzani
Study does not mention how much Omega-3 was used, nor for how many days
- Sepsis is both prevented and treated by Vitamin D 8 fewer ICU days with Vitamin D – RCT
Wonder how many fewer days if use BOTH Vitamin D and Omega-3
- Overview: Omega-3 many benefits include helping vitamin D
- Sepsis reduced the Omega-3 response and half life – April 2019
- Omega-3 reduced pancreas transplant failure by 3X and sepsis by 2X – review Dec 2019
- Little risk of infection after surgery if have more than 50 ng of vitamin D - 2014
- Vitamin D reduces inflammation in critically ill patients – Sept 2020
- Role and Mechanism of Vitamin D in Sepsis (Chinese) – Feb 2020
- Vitamin D, glutathione, and heat shock protein to treat concussions, etc. – US Patent Dec 2019
- Septic children have low Vitamin D (54 studies, ignored Vitamin D Receptor) – meta-analysis April 2019
- Urinary sepsis – a single Vitamin D injection reduced hospital days by 40 percent – RCT April 2018
- Vitamin D deficiency with severe sepsis increased risk of dying by 7.7 X – Nov 2017
- Severe sepsis may be prevented by 400,000 IU of vitamin D – RCT 2023
- Sepsis was present in 6 percent of US adult hospitalizations – JAMA Oct 2017
- 2.7 fewer days in hospital after surgery if had taken Omega-3 (19 RCT) – meta-analysis – June 2017
- Sepsis: 4 fewer days in ICU if add Omega-3 – meta-analysis of 12 RCT – June 2017
- Pro-inflammatory cytokines cause the 74 percent drop in vitamin D after knee arthroplasty – Feb 2014
- Critically ill patients with low vitamin D were 13X more likely to have a lot of mitrocondrial DNA in blood – Sept 2014
- More sepsis deaths when active vitamin D (Calcitrol) was low – May 2013
- Vitamin D decrease during inflammation is probably due to interferons - Oct 2012
- Sepsis is both prevented and treated by Vitamin D
- Inflammation or surgery or heart attack decreases measured vitamin D levels – Mar 2011
Nutritional supplementation of omega-3 fatty acids has been proposed to modulate the balance of pro- and anti-inflammatory mediators in sepsis. If proved to improve clinical outcomes in critically ill patients with sepsis, this intervention would be easy to implement. However, the cumulative evidence from several randomized clinical trials (RCTs) remains unclear.
We searched the Cochrane Library, MEDLINE, and EMBASE through December 2016 for RCTs on parenteral or enteral omega-3 supplementation in adult critically ill patients diagnosed with sepsis or septic shock. We analysed the included studies for mortality, intensive care unit (ICU) length of stay, and duration of mechanical ventilation, and used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the quality of the evidence for each outcome.
A total of 17 RCTs enrolling 1239 patients met our inclusion criteria. Omega-3 supplementation compared to no supplementation or placebo had no significant effect on mortality [relative risk (RR) 0.85; 95% confidence interval (CI) 0.71, 1.03; P = 0.10; I 2 = 0%; moderate quality], but significantly reduced ICU length of stay [mean difference (MD) −3.79 days; 95% CI −5.49, −2.09; P < 0.0001, I 2 = 82%; very low quality] and duration of mechanical ventilation (MD −2.27 days; 95% CI −4.27, −0.27; P = 0.03, I 2 = 60%; very low quality). However, sensitivity analyses challenged the robustness of these results.
Omega-3 nutritional supplementation may reduce ICU length of stay and duration of mechanical ventilation without significantly affecting mortality, but the very low quality of overall evidence is insufficient to justify the routine use of omega-3 fatty acids in the management of sepsis.
- Singer M, Deutschman CS, Seymour C, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801-10.
- Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.
- Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787-94.
- Vincent JL, Marshall JC, Namendys-Silva SA, Francois B, Martin-Loeches I, Lipman J, et al. Assessment of the worldwide burden of critical illness: the intensive care over nations (ICON) audit. Lancet Respir Med. 2014;2(5):380-6.
- Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlatt- mann P, et al. Assessment of global incidence and mortality of hospital- treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med. 2016;193(3):259-72.
- Preiser JC, van Zanten AR, Berger MM, Biolo G, Casaer MP, Doig GS, et al. Metabolic and nutritional support of critically ill patients: consensus and controversies. Crit Care (London, England). 2015;19:35.
- Green P, Theilla M, Singer P. Lipid metabolism in critical illness. Curr Opin Clin Nutr Metab Care. 2016;19(2):111-5.
- Martin JM, Stapleton RD. Omega-3 fatty acids in critical illness. Nutr Rev. 2010;68(9):531-41.
- Whelan J, Broughton KS, Kinsella JE. The comparative effects of dietary alpha-linolenic acid and fish oil on 4- and 5-series leukotriene formation in vivo. Lipids. 1991;26(2):119-26.
- Zhao Y, Joshi-Barve S, Barve S, Chen LH. Eicosapentaenoic acid prevents LPS-induced TNF-a expression by preventing NF-kB activation. J Am Coll Nutr. 2004;23(1):71-8.
- Ariel A, Serhan CN. Resolvins and protectins in the termination program of acute inflammation. Trends Immunol. 2007;28(4):176-83.
- Pontes-Arruda A, Demichele S, Seth A, Singer P. The use of an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data. JPEN J Parenter Enteral Nutr. 2008;32(6):596-605.
- Gadek JE, DeMichele SJ, Karlstad MD, Pacht ER, Donahoe M, Albertson TE, et al. Effect of enteral feeding with eicosapentaenoic acid, gamma- linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral nutrition in ARDS Study Group. Crit Care Med. 1999;27(8):1409-20.
- Heller AR, Rossler S, Litz RJ, Stehr SN, Heller SC, Koch R, et al. Omega-3 fatty acids improve the diagnosis-related clinical outcome. Crit Care Med. 2006;34(4):972-9.
- Grau-Carmona T, Bonet-Saris A, Garcia-de-Lorenzo A, Sanchez-Alvarez C, Rodriguez-Pozo A, Acosta-Escribano J, et al. Influence of n-3 polyunsaturated fatty acids enriched lipid emulsions on nosocomial infections and clinical outcomes in critically ill patients: ICU lipids study. Crit Care Med. 2015;43(1):31-9.
- Zhu D, Zhang Y, Li S, Gan L, Feng H, Nie W. Enteral omega-3 fatty acid supplementation in adult patients with acute respiratory distress syndrome: #a systematic review of randomized controlled trials with meta-analysis and trial sequential analysis. Intensive Care Med. 2014;40(4):504-12.
- Santacruz CA, Orbegozo D, Vincent JL, Preiser JC. Modulation of dietary lipid composition during acute respiratory distress syndrome: systematic review and meta-analysis. JPEN J Parenter Enteral Nutr. 2015;39(7):837-46.
- Palmer AJ, Ho CK, Ajibola O, Avenell A. The role of omega-3 fatty acid supplemented parenteral nutrition in critical illness in adults: a systematic review and meta-analysis. Crit Care Med. 2013;41(1):307-16.
- 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(1):20-8.
- Rice TW, Wheeler AP Thompson BT, deBoisblanc BP Steingrub J, Rock P. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306(14):1574-81.
- Hall TC, Bilku DK, Neal CP, Cooke J, Fisk HL, Calder PC, et al. The impact of an omega-3 fatty acid rich lipid emulsion on fatty acid profiles in critically ill septic patients. Prostaglandins Leukot Essent Fatty Acids. 2016;112:1-11.
- Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ (Clinical Research ed). 2011;343:d5928.
- DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-88.
- Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration; 2011. http://www.handbook.cochrane.org.
- Hosny M, Nahas R, Ali S, Elshafei SA, Khaled H. Impact of oral omega-3 fatty acids supplementation in early sepsis on clinical outcome and immunomodulation. Egypt J Crit Care Med. 2013;1(3):119-26.
- Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clinical Research ed). 2003;327(7414):557-60.
- Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ (Clinical Research ed). 2008;336(7650):924-6.
- Bower RH, Cerra FB, Bershadsky B, Licari JJ, Hoyt DB, Jensen GL, et al. Early enteral administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: results of a multicenter, prospective, randomized, clinical trial. Crit Care Med. 1995;23(3):436-49.
- Burkhart CS, Dell-Kuster S, Siegemund M, Pargger H, Marsch S, Strebel SP et al. Effect of n-3 fatty acids on markers of brain injury and incidence of sepsis-associated delirium in septic patients. Acta Anaesthesiol Scand. 2014;58(6):689-700.
- Galban C, Montejo JC, Mesejo A, Marco P Celaya S, Sanchez-Segura JM, et al. An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Crit Care Med. 2000;28(3):643-8.
- Grau-Carmona T, Moran-Garcia V, Garcia-de-Lorenzo A, Heras-de-la-Calle G, Quesada-Bellver B, Lopez-Martinez J, et al. Effect of an enteral diet enriched with eicosapentaenoic acid, gamma-linolenic acid and antioxidants on the outcome of mechanically ventilated, critically ill, septic patients. Clin Nutr (Edinburgh, Scotland). 2011;30(5):578-84.
- Grecu I, Mirea L, Grintescu I. Parenteral fish oil supplementation in patients with abdominal sepsis. Clin Nutr. 2003;22:S23.
- Hall TC, Bilku DK, Al-Leswas D, Neal CP Horst C, Cooke J, et al. A randomized controlled trial investigating the effects of parenteral fish oil on survival outcomes in critically ill patients with sepsis: a pilot study. JPEN J Parenter Enteral Nutr. 2015;39(3):301-12.
- Khor BS, Liaw SJ, Shih HC, Wang LS. Randomized, double blind, placebo- controlled trial of fish-oil-based lipid emulsion infusion for treatment of critically ill patients with severe sepsis. Asian J Surg Asian Surg Assoc. 2011;34(1):1-10.
- Pontes-Arruda A, Aragao AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med. 2006;34(9):2325-33.
- Pontes-Arruda A, Martins LF, de Lima SM, Isola AM, Toledo D, Rezende E, et al. Enteral nutrition with eicosapentaenoic acid, y-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT Study. Crit Care. 2011;15(3):R144.
- Shirai K, Yoshida S, Matsumaru N, Toyoda I, Ogura S. Effect of enteral diet enriched with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with sepsis-induced acute respiratory distress syndrome. J Intensive Care. 2015;3(1):24.
- Gultekin G, Sahin H, Inanc N, Uyanik F, Ok E. Impact of Omega-3 and Omega-9 fatty acids enriched total parenteral nutrition on blood chemistry and inflammatory markers in septic patients. Pak J Med Sci. 2014;30(2):299-304.
- Qu A, Xu L. Yuyou zhifang ru dui nong du zheng huanzhe mianyi gongneng de tiaojie zuoyong guancha (Regulation of fish oil fat emulsion on immune function in patients with sepsis). Shandong Med J. 2009;49(6):13-5.
- Wu YY w-3-duo bu baohe zhifangsuan dui nong du zheng huanzhe mianyi gongneng ji yuhou de yingxiang (Omega-3 polyunsaturated fatty acids on immune function and prognosis in patients with sepsis) (Master's thesis). Hebei Medical University; 2010.
- Zhao K, Zhou W, Bo C. w-3 yuyou zhifang ru dui nong du zheng huanzhe de linchuang liaoxiao (Clinical efficacy of omega-3 fish oil fat emulsion in patients with sepsis). Shandong Med J. 2011;51(16):102.
- Guo Y w-3 duo bu baohe zhifangsuan dui nong du zheng huanzhe linchuang liaoxiao ji yuhou de yingxiang (Effect of omega-3 polyunsaturated fatty acids on clinical efficacy and prognosis in patients with sepsis). Shanxi Med J. 2008;37(15):727-9.
- Barbosa VM, Miles EA, Calhau C, Lafuente E, Calder PC. Effects of a fish oil containing lipid emulsion on plasma phospholipid fatty acids, inflammatory markers, and clinical outcomes in septic patients: a randomized, controlled clinical trial. Crit Care. 2010;14(1):R5.
- Tao W, Li P-S, Shen Z, Shu Y-S, Liu S. Effects of omega-3 fatty acid nutrition on mortality in septic patients: a meta-analysis of randomized controlled trials. BMC Anesthesiol. 2015;16:39.
- Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-12.
- Friesecke S, Lotze C, Kohler J, Heinrich A, Felix SB, Abel P. Fish oil supplementation in the parenteral nutrition of critically ill medical patients: a randomised controlled trial. Intensive Care Med. 2008;34(8):1411-20.
- Mo Y, Hu X, Chang L, Ma P. The effect of omega-3 fatty acid supplementation in parenteral nutrition on the outcome of patients with sepsis: a systematic review and meta-analysis. Chin Crit Care Med. 2014;26(3):142-7.
- Jurewitsch B, Gardiner G, Naccarato M, Jeejeebhoy KN. Omega- 3-enriched lipid emulsion for liver salvage in parenteral nutrition- induced cholestasis in the adult patient. JPEN J Parenter Enteral Nutr. 2011;35(3):386-90.
- Atkinson S, Sieffert E, Bihari D. A prospective, randomized, double-blind, controlled clinical trial of enteral immunonutrition in the critically ill. Guy's Hospital Intensive Care Group. Crit Care Med. 1998;26(7):1164-72.
- Manzanares W, Langlois PL, Dhaliwal R, Lemieux M, Heyland DK. Intravenous fish oil lipid emulsions in critically ill patients: an updated systematic review and meta-analysis. Crit Care (London, England). 2015;19:167.
- Chen W, Jiang H, Zhou ZY, Tao YX, Cai B, Liu J, et al. Is omega-3 fatty acids enriched nutrition support safe for critical ill patients? A systematic review and meta-analysis. Nutrients. 2014;6(6):2148-64.
- Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1.
- Rochwerg B, Alhazzani W, Jaeschke R. Clinical meaning of the GRADE rules. Intensive Care Med. 2014;40(6):877-9.