ESPEN Congress Geneva 2014 LLL LIVE COURSE: ICU NUTRITION AND PROBLEM SOLVING. Substitution, supplementation and pharmaco-nutrition M.

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1 ESPEN Congress Geneva 2014 LLL LIVE COURSE: ICU NUTRITION AND PROBLEM SOLVING Substitution, supplementation and pharmaco-nutrition M. Berger (CH)

2 Nutritional Support in Intensive Care Unit Patients Substitution, supplementation and pharmaco-nutrition Module 18.3 Pr. Mette M Berger Service of Adult Intensive Medicine & Burn Centre CHUV - Lausanne

3 Ethical dilemmas Bioethical principles Application of bioethical principles to Nutrition at the end-of-life The decision-making process

4 Specific substrates for artificial nutrition in the ICU Fatty acids: n-3 PUFA, MUFA Amino acids: Glutamine, Arginine, Leucine,.. Antioxidants: Selenium, Vit. C, Vit. E,

5 SOY n-6 pufa LIPIDS OLIVE n-9 mufa FISH. n-3 pufa

6 Classification Glyceride = glycerol containing lipid, Triglyceride = triesters of glycerol Fatty acid = long hydrocarbon chain organic acid, that are saturated or not Phospholipid lipids containing glycerol, phosphate, 2 fatty acids and x (choline, ethanolamine, serine, inositol)

7 Fatty acids H 3 C COOH 18:0 Stearic acid H 3 C 9 COOH 18:1ω-9 Oleic acid H 3 C 6 COOH 18:2ω-6 Linoleic acid H 3 C 3 COOH 18:3ω-3 α-linolenic acid Mammals cannot insert double bonds here

8 Clinical Nutrition 28 (2009) Lipids should be an integral part of PN for energy and to ensure essential fatty acid provision. I.V. lipid emulsions (LCT, MCT or mixed emulsions) can be administered safely at a rate of 0.7 g/kg up to 1.5 g/kg over 12 to 24 h. Olive oil-based PN is well tolerated in critically ill patients. 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. B B B B

9 Choosing the lipid: A key consideration in PN Industry proposes different levels of SFAs, PUFAs, and MUFAs 1,2 Oil source / % FA Intralipid 20% 1 100% soy 50% coconut 50% soy Lipofundin MCT/LCT Structolipid 20% 1 20% 1 36% coconut 64% soy Omegaven ClinOleic Lipoplus SMOFlipid 10% 1 20% 1 20% 2 20% 1 100% fish 80% olive 20% soy 50% coconut 40% soy 10% fish 30% soy 30% coconut 25% olive 15% fish SFA MUFA PUFA ω ω ω MCT, medium-chain triglyceride; LCT, long-chain triglyceride. 1. Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5): Driscoll DF. Nutr Clin Pract. 2006;21(4):

10 Ubiquitous effect of n-3 FA

11 N-3 PUFA and immunity Buckley CD et al, Immunity,

12 ω-3 PUFAs Hyper Inflammation HYPER INFLAMMATION Excess inflammatory eicosanoids, cytokines, ROS, adhesion molecules; NFkB activation POOR OUTCOME Hypo INSULT IMMUNO SUPPRESSION Excess anti-inflammatory Cytokines; Suppressed HLA expression & antigen presentation; Suppressed T cell function

13 Resolution of Acute Inflammation Host Defense Injury/trauma Microbial infection Chemical stimuli Acute Inflammation Neutrophil Pro-Resolution Programs New Terrain Chronic Inflammation Pro-inflammatory Mediators Classic Leukotrienes Prostaglandins Resolution Protective Lipid Mediators Resolvins [Rv] Protectins [PD] Lipoxins [LX] Aspirin-triggered Lipoxins [ATL]

14 Barbosa et al, Critical Care 2010; 14:R5 Effects of a fish oil emulsion on plasma phospholipid fatty acids, inflammatory markers, and clinical outcomes in septic patients. A randomized, controlled, clinical trial, N=25 50:50 mixture: MCT, LCT or 50:40:10 mixture: MCT, LCT + FO PO2/FiO p = MCT / LCT 150 MCT / LCT / FO Day 1 Day 6

15 Effects of a fish oil emulsion on plasma phospholipid fatty acids, inflammatory markers, and clinical outcomes in septic patients. A randomized, controlled, clinical trial, N=25 Barbosa et al, Critical Care 2010 Proportion of patients with PO 2 /FiO 2 < 200 and < 300 at day 6 100% 90% 80% p = p = % 60% 50% 40% 60% 70% MCT / LCT MCT / LCT / FO 30% 36% 20% 10% 0% 0% PO2 /FiO2 < 200 PO2 /FiO2 < 300

16 Safety and efficacy of fish oil-enriched PN regimen on postoperative patients undergoing major abdominal surgery Fish-Oil enriched PN - Infections Chen et al, JPEN 2010

17 Safety and efficacy of fish oil-enriched PN regimen on postoperative patients undergoing major abdominal surgery Fish-Oil enriched PN - LICUS Chen et al, JPEN 2010

18 Safety and efficacy of fish oil-enriched PN regimen on postoperative patients undergoing major abdominal surgery Fish-Oil enriched PN - LHOS Chen et al, JPEN 2010

19 Role of PN in etiology and pathogenesis of liver disease Absence of enteral feeding Reduction in bile flow cholestasis Bile acid toxic to hepatocyte, inflammation mediated by cytokines from activated macrophages Diminished gut motility, more bacterial overgrowth and translocation Excess provided by PN Excess total calorie intake, CHO (>50 kcal/kg/day) Excess lipid (> 1g/kg/day) Excess Mn, phytosterol, methionine

20 Hepatocellular integrity after PN: comparison of a FOlipid emulsion with an olive-soybean oil emulsion. Piper et al, Eur J Anaesthesiol. 2009;26: postop patients with indication for PN (for 5 days)

21 Prevention of PN-associated liver disease: role of ω-3 FO Fallon E et al, CO in Organ Transplantation. 2010, 15: FO Fig. 2 Trends over time of markers of liver dysfunction in fish oil versus soybean oil cohorts FO

22 Impact of Fish Oil-Based Lipid Emulsion on Serum Triglyceride, Bilirubin, and Albumin Levels in Children with PN Liver Disease Lee et al, Pediatr Res, 2009;66:698 FO n=18 Soy-Bean n=59 fish oil = dots, soybean oil = stars Individual trajectory of TG after beginning fish oil week 19 Observed weekly geometric mean

23 N=44, double-blind randomized trial. Omegaven gr (0.2g) post-op vs control group. Reduced ASAT, ALAT, bilirubin, lipase. Maintained weight in FO g vs kg loss in SO g.

24 Combination of EPA/GLA and antioxidant vitamins on mortality 2007 taken from Canadian Clinical Practice Guidelines

25 A.S.P.E.N and SCCM Guidelines for the Use of Parenteral and Enteral Nutrition In Adult and Pediatric Patients * position about the EPA+GLA formula? Patients with ARDS and severe acute lung injury (ALI) should be placed on an enteral formulation characterized by an anti-inflammatory lipid profile (ie, omega-3 fish oils, borage oil) and antioxidants. (Grade:A) Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN 2009;

26 Enteral n-3 Areas of controversy Choice of control formula - 3 of 5 studies used high fat (omega-6-fa) as control: Positive results in the EPA/GLA! (Gadek 1999, Singer 2006, Pontes Arruda 2006) - 2 studies used low fat (omega-6-fa) as control: No benefit! But enteral administration was as a bolus! (Rice 2011, Stapleton 2011) Good studies vs doubtful studies - 1 Study with recruitment problems: Positive results! (INTERCEPT Pontes Arruda 2011) - 1 Good new study: No benefit! (Grau-Carmona 2011)

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28 A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury. Stapleton et al

29 Stapleton et al CCM, 2011 Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with ALI

30 Main difference with previous studies Enteral or parenteral feeding was at the discretion of treating clinicians Standard feeding solution EN started 1.8±1.2 (FO) and 1.9±1.3 days after ICU admission (p=0.65). Mean caloric intake during the study s first week was 7362±3800 kcal (1051 kcal/d) in the fish oil group and 7495±3831 kcal (1070 kcal/d) in the placebo group (p=0.87).

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32 Rice et al, JAMA 2011

33 Enteral Omega-3 Fatty Acid, γ-linolenic Acid, and Antioxidant Supplementation in Acute Lung Injury Rice et al, JAMA 2011, 306: 1574 OMEGA study, a randomized, double-blind, placebo-controlled, multicenter trial: 272 adults within 48 hours of developing ALI requiring mechanical ventilation 2-daily enteral supplement of n-3 PUFAs, γ-linolenic acid, and AOXs compared with an isocaloric control The study was stopped early for futility after 143 and 129 patients were enrolled

34 5 x more protein in the control group!!! Underfeeding in both groups Bolus feeding

35 n-3 fatty acid-enriched PN regimens in elective surgical and ICU patients: a meta-analysis Pradelli et al, CritCare, 2012; 16:R184 Σ 23 studies (n = 1502 patients: n = 762 admitted to the ICU) No significant in mortality rate between patients on n-3 PUFA-enriched PN vs. standard PN (RR= 0.89; 0.59, 1.33) low underlying mortality risk? But.. Infections, LOS, inflammation, lung gas exchange, liver function, antioxidant status, plasma FA, ( impairment of kidney function?) Infections

36 LOS n-3 fatty acid-enriched PN regimens in elective surgical and ICU patients: a meta-analysis Pradelli et al, CritCare, 2012; 16:R184

37 The Effects of different IV Fat Emulsions on Clinical Outcomes in Critically Ill Patients Edmunds et al CCM, 2014: 42:1168 INS = International Nutrition Survey

38 The Effects of different IV Fat Emulsions on Clinical Outcomes in Critically Ill Patients Edmunds et al CCM, 2014: 42:1168 Adult patients who were admitted to the ICU for more than 72 hours, were mechanically ventilated within 48 hours, received exclusive PN for > 5 days, and did not change IV fat emulsion type during the data collection period Cumulative hazard curve of the likelihood of patients being discharged from ICU alive for comparison of lipid free versus each IV fat emulsion category (p < 0.001).

39 Conclusion n-3 PUFA n-3 PUFA supplementation in TPN shown to: - be safe and well tolerated - rapidly increase n-3 fatty acids in cell membranes Exert anti-inflammatory and immunomodulatory effects complication rate (surgical patients) length ICU and hospital stay (surgical patients) As part of enteral nutrition n-3 PUFA provide the benefits of a balanced diet

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41 Glutamine in the ICU Glutamine is the most abundant amino-acid in the body Muscle represents the major body protein pool Semi-essential amino-acid during stress Primary fuel for all rapid proliferating cells (enterocytes, lymphocytes, etc.) Helps to maintain gut integrity Reduces muscle degradation Not contained in industrial PN solutions (stability issue) while present in EN (tiny amounts)

42 Critical illness is associated with low plasma levels in most patients Critical illness Glutamine (mcmol/l) Bone marrow TX Sepsis Trauma Burns Acute pancreatitis Brown et al 1998 Mc Burney et al 1994 Griffiths et al 1997 Houdjik er al 1998 Jensen et al 1996 Jones et al 1999 Schelting et al 1991 Roth et al 1986 Schloerb et al 1999 Schloerb et al 1993 Ziegler et al 1992 Newsholme et al 1987 Powell-tuck et al 1999 Rennie et al 1985 Roth et al 1990 Tremel et al 1994 Chemotherapy Decker-Baumann et al 1989 Surgical patients Hammarquvist et al 1989 Jrang et al 1999 Morillon et al 1996 O Riordin et al 1994 Stehle et al 1989

43 ESPEN Guidelines on Enteral Nutrition: Intensive care Kreymann G et al, Clin Nutr 2006 ESPEN Guidelines on Parenteral Nutrition: Intensive care Singer P et al Clin Nutr 2009

44 A randomized trial of i.v. GLN supplementation in trauma ICU patients Pérez-Barcena et al, ICM 2014: 40:539 PRCT: GLN not given as a component of nutrition but as an extra infusion (0.35 g of L-glutamine/kg BW/day) in 142 ICU trauma patients. Primary outcome = n new infections first 14 days No difference in infection rates for the global population EN Placebo 46 (65.7) GLN 41 (58.6) PN 7 (10.0) 7 (10.0) Both EN-PN: 18 (24.3) 23 (31.4) Patients with low glutamine levels at day 6 had more infections (58.8 vs %; p = 0.032), longer LICU (9 vs. 20 days; p<0.01) and LOS (24 vs. 41 days; p = 0.01)

45 Parenteral glutamine supplementation in critical illness: a systematic review Wischmeyer et al, CritCare, 2014; 18:R76 MORTALITY

46 Parenteral glutamine supplementation in critical illness: a systematic review Wischmeyer et al, CritCare, 2014; 18:R76 HOSPITAL MORTALITY reported in 13 studies

47 Parenteral glutamine supplementation in critical illness: a systematic review Wischmeyer et al, CritCare, 2014; 18:R76 INFECTIONS

48 REDOXS Heyland et al, NEJM 2013 PRCT: April 2005 and December 2011 in 40 international ICUs Randomized within 18 hours of admission 2x2Factorial design n=1218 Patient Characteristics PLACEBO GLN AOX AOX+GLN n Inclusion criteria A PaO 2 /FiO 2 ratio (94.0%) 285 (94.7%) 287 (93.5%) 285 (91.9%) Clinical evidence of hypo-perfusion 277 (92.3%) 278 (92.4%) 286 (93.2%) 293 (94.5%) Renal dysfunction 104 (34.7%) 117 (38.9%) 99 (32.2%) 122 (39.4%) Platelet count of 50 x 10 9 /L 16 (5.3%) 21 (7.0%) 12 (3.9%) 18 (5.8%) Hours in ICU prior to randomization First organ dysfunction to initiation of parenteral supplements (hours) First organ dysfunction to initiation of EN (hours) n [16.5 to 26.5] 22.0 [12.5 to 36.8] 21.0 [14.8 to 25.0] 21.0 [11.1 to 35.0] 21.1 [16.0 to 25.5] 20.4 [12.0 to 34.8] 21.5 [16.3 to 26.0] 20.0 [11.8 to 36.2]

49 Glutamine que passa? Death rate AOX Yes No GLN Yes 31% 31% No 27.6% 24.5% REDOXS: highest dose ever 0.78 g/kg/d very early (<24hrs) during shock phase, no deficit P=0.06

50 GNL 3 or more organ failures chi 2 P = n = 611 NoGln n = 607 By courtesy Prof Jan Wernerman

51 Specificities of REDOXS Very sick patients: > 2 organ failures, 35 % ARF Total Dose 0.78 g/kg > recommendations Very early delivery of a full GLN dose WITHOUT feeding: mean nutrition US 40% of target Mortality Predicrs: >2 organ failures, ARF, <30% of energy delivery, steroids, vasopressors

52 Role of Glutamine Supplementation in Critical Illness Given the Results of the REDOXS Study Heyland & Dhaliwal, JPEN 2013: in press

53 Nutrition in ICU Antioxidants 1. Oxidative stress is increased in critically ill patients and contributes to organ damage / malignant inflammation. 2. As the increase in oxidative stress is associated with depletion of the stores of anti-oxidants, the administration of antioxidants can be beneficial 3. Adding anti-oxidant compounds to nutrition support is physiological.

54 Plasma redox status relates to severity in critically ill patients Alonso de Vega J et al, CCM 28:1812, 2000 APACHE III scores and plasma redox status (r 2 = 0.56; p <.001) as defined by the ratio total antioxidant capacity (mm) / lipoperoxides (um) APACHE III scores and plasma myeloperoxidase concentrations (r 2 = 058; p <.001) 73 patients at admission to a mixed ICU: 8 deaths

55 Oxidative stress and metallothionein expression - liver of rats with severe thermal injury Ding et al Burns, 28:215, 2002 Effects of severe thermal injury on the zinc concentrations both in the serum and in the liver. mean±sem, n=5. * P<0.001, ** P<0.01 and # P<0.05 vs. the corresponding normal control

56 Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients Forceville X et al, CCM 26:1536, 1998 Admission plasma [Se] related to severity of sepsis

57 Replacement of losses Objective = restore a biological function Major burns Major trauma CVVH Intestinal losses Isolated deficit

58 Trace element (Cu,Se,Zn) substitution in Burns Reduction of nosocomial pneumonia Berger et al, 2006, Crit Care 10:R153 Aggregation of 2 consecutive Randomized Trials IV - Cu 3 mg - Se 300 mcg - Zn 30 mg 65% reduction of pneumonia risk Log Rank p= Wilcoxon p= n = 41 Burns 46% BSA

59 AOX trial critically ill: trauma-cardiac-sah Se, Zn, Vit E, Vit C, Vit B1 Berger et al Crit Care :R days

60 Impact of high-dose antioxidants on outcomes in acutely injured patients Collier and all, JPEN 2008 Retrospective study, before / after TTT: vitamin C 1g, E 1000 ui, selenium 200 mcg Results: 4,294 patients (AO+, N = 2,272; AO-, N = 2022). Hospital (4 vs 3 days, P <.001) and ICU stay (3 vs 2 days, P =.001) median length of stays were significantly shorter in the AO+ group. Mortality significantly lower in the AO+ group (6.1% vs 8.5%, P =.001), translating into a 28% RR reduction for mortality with AOX After adjusting for age, gender, and probability of survival, AO exposure was associated with even lower mortality (OR 0.32, 95% CI ). Patients with an expected survival <50% benefited most high-dose AOX protocol a 28% RR in mortality and a significant in both hospital and ICU length of stay. Inexpensive intervention to reduce mortality/morbidity in trauma patients.

61 High-dose antioxidant administration is associated with a reduction in post-injury complications in critically ill trauma patients Giladi AM et al Int. J. Care Injured 42 (2011) 78 82

62 Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis Manzanares et al. Critical Care 2012, 16:R66 Effects of AOX on mortality n=20 studies AOX

63 Current recommendations Source ASPEN SCCM Canadian GL ESPEN May 09 Jan (EN) 09 (PN) A combination of AOX vitamins and trace minerals (specifically including selenium) should be provided to all critically ill patients receiving specialized nutrition therapy. (Grade: B) Based on 3 level 1 and 13 level 2 studies, the use of supplemental combined vitamins and trace elements should be considered in critically ill patients. There are insufficient data to make a recommendation regarding IV/PN selenium supplementation, alone or in combination with other antioxidants, in ICU patients. Burns : Trace elements (Cu, Se, Zn) should be supplemented in a higher than standard dose (A). Any prescription of PN includes 1 daily dose of multivitamins and 1 daily dose of trace elements (C).

64 Adjuvant selenium supplementation in the form of sodium selenite in postoperative critically ill patients with severe sepsis Sakr et al, Critical Care 2014, 18:R68 retrospective study, all adult patients admitted to a 50-bed surgical ICU with severe sepsis (January 2004 April 2010) analysis: whether or not received adjuvant Se supplementation (given at the discretion of the attending physician). Se was administered in the form of Na selenite pentahydrate (Na 2 SeO 3.5H 2 O): 100 μg of Se 333 μg of sodium selenite. A bolus of Na selenite corresponding to 1000 μg of Se was injected IV through a central venous line over 30 minutes followed by infusion of 1000 μg/day over 24 hours for 14 days ICU discharge or death. Adjuvant Se in 413 (39.7%) of the 1047 severe sepsis patients. Se supplementation was not independently associated with favorable outcome (OR = 1.19, 95% CI: 0.86 to 1.65, P = 0.288) Jena Germany 46 vs 39.1%

65 REDOXS: A randomized trial of high dose Glutamine and Antioxidants in critically ill patients with MOF Heyland et al, NEJM 2013 Antioxidant vs. no- AOX n=1218 No effect Kaplan-Meier 6 Month Survival curves

66 Replace or supplement? 2 distinct aims Toxicity? Supplement normal Losses +++ Insufficient Intakes Deficit Replace + +++

67 Dose response curve Biologiccal activity A+B+C deficieny, D suboptimal, E optimal, G toxicity, H lethal

68 Selenium and human health Rayman M, Lancet adult participants Study participants were recruited from 1988 to 1994 Adjusted hazard ratios for all-cause mortality by serum selenium concentration in adult participants of the US 3rd National Health & Nutrition Examination Survey followed up for up to 18 years until the end of Shaded area: 95% CIs. Reference value (hazard ratio 1) set at the 10th percentile of the serum selenium distribution (105,8 μg/l) (Bleys et al 2008)

69 Conclusions n-3 PUFA: Strong positive evidence in surgical and ICU patients Glutamine: Strong nutritional evidence for parenteral in ICU patients, Limited evidence for enteral Glutamine except Burns, Trauma Antioxidant micronutrients : differentiate repletion from supplementation!! more PRCTs are required for general ICU patients strong evidence in burns and trauma patients

70 High protein Immune enhancing vs. high protein EN & Nosocomial Infections in the ICU van Zanten ARH et al, JAMA 2014;312: adult patients, expected to be ventilated for >72hrs and to require EN for >72 hrs were randomized to the IMHP (n = 152) or HP (n = 149). EN initiated within 48 hrs of ICU admission for ICU stay IMPH glutamine,omega-3 fatty acid, and antioxidant enriched tube feed MetaPlus

71 High protein Immune enhancing vs. high protein EN & Nosocomial Infections in the ICU van Zanten ARH et al, JAMA 2014;312:514 Result: no significant in incidence of new infections between groups: IMHP - 53%(95%CI, 44%-61%) vs HP 52% (95%CI, 44%-61%) (P =.96) MetaPlus