1. Latest Evidence on Nutrition in the ICU: Will it Change Existing Guidelines? Rupinder Dhaliwal, RD Clinical Evaluation Research Unit Critical Care Nutrition Kingston ON, Canada 1

2. Outline of Session New RCTs in select area of critical care nutrition (adult)  Fish oils  Parenteral glutamine  Antioxidants  Probiotics Updated analyses of Canadian Guidelines Impact on evidentiary basis 1

3. Conflict of interest Co-author of Canadian Clinical Practice Guidelines 1

4. www.criticalcarenutrition.com JPEN 2003  1980-2003  n > 200 RCTs  34 topics  17 recommendations 2005 update 2007 update 2009 update

5. Development of Guidelines Validity Homogeneity Safety Feasibility Cost evidenceintegration of values + practice guidelines 1

6. Inclusion Criteria Updated to 2012 Randomized controlled trials Critically ill patients (not elective surgery) Clinical Outcomes EMBASE, Medline, Cinhal, reference lists

7. Topic# RCTs 2009# new RCTs 2012 Early vs. delayed142 Target dose EN22 Fish Oils/Borage Oils54 Protein/peptides41 Fibre61 Small Bowel vs. Feeding115 Protocols/GRVs32 Probiotics127 Supplemental PN55 PN Type of lipids54 PN Glutamine1711 Antioxidants166 PN Selenium115 New RCTs per Topic (n = 66)

8. New Topic# new RCTs Trophic vs. Full feeds2 Hypocaloric EN1 Fish Oils only1 PN + EN Glutamine1 Threshold of GRVs1 Discarding GRVs1 Early Supplemental PN vs Late1 Vitamin D1 New Topics (n=8) and RCTs

9. Enteral Fish Oils* *Product enhanced with fish oils +borage oils + antioxidants 1

10. Enteral Fish Oils* *Product enhanced with fish oils +borage oils + antioxidants 2009 Recommendation Based on 5 studies, we recommend the use of enteral formula with fish oils, borage oils, and antioxidants in patients with ALI/ARDS New RCTs = 3 Rice 2011 Grau-Carmona 2011 Thiella 2011 + Pontes Arruda 2011 + Stapleton 2011 (fish oil only)

11.  Multicenter, RCT, 14 ICUs in Brazil  N = 200, early stages of sepsis (no organ failures; within 36 hrs from onset of sepsis).  Fish oil/borage oil/antioxidant vs. standard polymeric X 7 days  Outcomes: Evolution to more severe forms of sepsis (severe sepsis or septic shock 28 day all-cause mortality, organ failure development, hyper/hypoglycemic events, insulin use, hospital stay, ICU stay Pontes-Arruda Crit Care 2011;15:R144

12. Variable Study (n=53) Control (n=53) P Value Use of mechanical ventilation, n (%) Development of sepsis5.7%13.3% 0.022 Development of septic shock20.7 %37.7% Invasive10 (18.9%)18 (34%).039 Non-invasive5 (9.4%)6 (11.3%)NS Number of days using mechanical ventilation 7 (4-12)15 (9-21).0033 Number of ICU days7 (4-12)13 (9-18)<.0001 Number of hospital days9 (6-14)19 (13-24)<.0001 Outcomes No difference in survival between the groups Pontes-Arruda Crit Care 2011;15:R144 PREVENTION VS. TREATMENT < 50 % patients ventilated Exclude from CPGs

13.  11 Spanish ICUs  89 patients with diagnosis of Sepsis on admission  Randomized to: Fish Oil/Borage Oil formula OR Standard polymeric formula  Outcomes: new organ dysfunction Grau-Carmona Clin Nutr 2011

14. Clinical Outcomes Grau-Carmona Clin Nutr 2011 Fish Oils: Trend towards lower SOFA scores (NS)

15. Timing of Feeding SUPPLEMENT “Early Full” Fast ramp up “Early Trophic” (10 ml/hr) N-3 + GLA + Antioxidants (Module delivered as bolus bid) Control Standard EN (480 cal/ 20 g pro) n = 250 NIH NHLBI

16. ……..Because of different study design, difficult to combine with other studies of continuous administration in moderately well fed patients….. Cook, Heyland JAMA Oct 2011

17. OMEGA: 60-Day Mortality P=0.05 P=0.14 Rice et al JAMA Oct 2011 bolus not formula select patients include but analyze without

18.  89 patients from 5 centres in US  Mechanically ventilated patients with Acute lung injury (ALI)  Randomized to (separate from EN): BOLUS fish oils 7.5 mls q 6 hrs, 9.75g EPA & 6.75 gm DHA/day OR placebo i.e. normal saline X 14 days  EN or PN as per MDs discretion Stapleton CCM 2011

19. Clinical Outcomes Stapleton CCM 2011 Fish Oils ONLY Bolus Separate from EN X aggregate with RCTs of fish oil, borage oil

20. Fish Oils: Effect on mortality (n = 6) 2009: RR 0.67, 95% CI 0.51, 0.97, p = 0.003 No effect, statistical heterogeneity! INTERSEPT, Stapleton data not included

21. Fish oils: effect on mortality removing bolus RCT (n =5) 1

22. EN fish oils: with new RCTs Effect on mortality disappears when bolus study is included statistical heterogeneity present Effect on mortality is significant when bolus study excluded 2012 Recommendation Fish Oils/borage oil: Downgrade recommendation to “should be considered” Fish Oils alone: insufficient data

23. Arginine 2009 Recommendation Based on 22 studies, we recommend arginine and other select nutrients not be used for critically ill patients 1 New RCTs = 0 Elective surgery patients many RCTs

24. Drover et al Am Coll Surg 2011 significant reduction in infections p <0.0001 significant shorter HLOS p <0.0001

25. Glutamine supplementation? 1

26. EN Glutamine 2009 Recommendation Based on 2 level 1 and 7 level 2 studies, enteral glutamine should be considered in burn and trauma patients. There are insufficient data to support the routine use of enteral glutamine in other critically ill patients No changes in recommendation New RCTs = 0

27. PN Glutamine 2009 Recommendation Based on 17 studies, when parenteral nutrition is prescribed to critically ill patients, parenteral supplementation with glutamine, where available, is strongly recommended. There are insufficient data to generate recommendations for intravenous glutamine in critically ill patients receiving enteral nutrition Ozgultekin 2008 Eroglu 2009 Perez Barcena 2010 Grau 2011 Andrews 2011 Wernerman 2011 Cekman 2011 Zeigler 2012 (in press) + 3 Chinese RCTs + Heyland 2012 REDOXS (EN + PN) New RCTs = 11

28. 10 centres in Scotland 502 Patients expected to be in ICU for at least 48h and required PN meet at least half their requirements (only 50% received PN) Randomized 2.6 days after admission to ICU Trial PN isocaloric and isonitrogenous, given for up to 7 days unless died or stopped PN »Glutamine 20g/d ( too small of a dose?) »Selenium 500μg/d »Both »Neither Median duration of study PN was 4-5 days Andrews BMJ 2011:342

29. The SIGNET Trial – RESULTS Effect of Glutamine No significant differences Confirmed infections within 14 days Mortality No significant differences

30.  Multicenter trial in Spain  127 patients with APACHE II score >12 and requiring PN for 5–9 days  Standard PN vs. Supplemented with 0.5 g/kg/d of Ala- Gln dipeptide  Enrolled patients received only 5-6 days of PN Grau CCM 2011; 39

31. P=0.10P=0.03 Grau CCM 2011; 39

32.  413 Patients given nutrition by EN and/or PN route  Within 72 hrs of ICU admission  Supplemented as IV L-Ala-Glutamine, 0.283 g/kg/day administered separate from PN vs. placebo (saline)  Primary endpoint SOFA; infections not recorded No effect on SOFA Wernerman Acta Anesthesiology 2011

33. PN glutamine group: lower mortality PP p = 0.046 ITT p = 0.098

34. Ahmet Eroglu Anesthesia Anal 2009 Critical Care 2010

35. GLND Ziegler et al (in press) n =150 surgical ICU patients needing PN after cardiac, vascular, colonic surgery no differences in mortality trend towards increase in infections

36. The REDOXS © Study REducing Deaths from OXidative Stress Dr. Daren Heyland et al N = 1223 patients with 2 or more organ failures Randomized to high GLN EN + PN vs. placebo within 24 hrs admission to ICU Factorial design: Antioxidants vs. placebo Glutamine given via PN plus EN Patients at least 2 Organ failure X aggregate with other studies

37. PN GLN: mortality revised (n = 24) 2009 RR 0.71 [0.55, 0.52] p = 0.008 2012 weaker now a trend

38. PN GLN: infections revised (n = 12) 2009 RR 0.76 (0.62, 0.93) p = 0.008 2012 still significant weaker

39. less effect on mortality, now only a trend less effect on infections, still significant 2012 Recommendation: PN Glutamine Downgrade to recommend or should be considered CAUTION: do not use high dose PN in patients with acute MOF PN + EN Glutamine (REDOXS) Strongly recommend that high dose IV GLN + EN NOT be used in patients with MOF PN GLN with new RCTs 1

40. Antioxidant supplementation Parenteral Selenium 1

41. Supplemental Antioxidant Nutrients 2009 Recommendation: Based on 16 studies, the use of supplemental vitamins and trace elements should be considered Parenteral Selenium 2009 Recommendation: There are insufficient data to make a recommendation regarding IV/PN selenium supplementation, alone or in combination with other antioxidants, in critically ill patients

42. AOX/PN Se new RCTs El Attar 2009 Montoya 2009 Andrews 2011 Manzanares 2011 Valenta 2011 New RCTs = 5 + REDOXS Study 2012 Manzanares Critical Care 2012

43. AOX combined: mortality, n =22 2009 0.76 RR [0.64, 0.91] p = 0.002 2012 still significant weaker signal

44. AOX combined: infections, n=11 2009 RR 0.94 [0.75, 1.17] p = 0.56 2012 stronger signal

45. AOX combined weaker significant effect on reduction on mortality stronger reduction in infections stronger signal for both in sicker patients PN selenium still trend towards reduction in mortality stronger reduction in infections 2012 Recommendation (TO BE FINALIZED): AOX: no change ? PN Se: no change ? Antioxidants/PN Se with new RCTs

46. Probiotics 1

47. 2009 Recommendation There are insufficient data to make a recommendation on the use of Prebiotics/Probiotics/Synbiotics in critically ill patients 1 Knight 2009 Barraud 2010 Morrow 2010 Frohmader 2010 Ferrie 2011 Sharma 2011 Tan 2011 New RCTs = 7 Petrof et al Critical Care 2012

48. Critical Care Medicine 2012

49. Probiotics with new RCTs stronger signal for reduction in infections (2009: no reduction) –higher quality studies do NOT show a reduction in infections significant reduction in VAP still trend towards reduction in ICU mortality 2012 Recommendation: Upgrade to should be considered 1

50. Summary Many recent RCTs in area of critical care nutrition Careful review of the articles is recommended Recommendations for following will probably not change Arginine EN glutamine Recommendations for the following will probably be downgraded EN Fish Oils/borage oils PN Glutamine PN + EN Glutamine (NEW TOPIC) Recommendations for following will probably be upgraded Probiotics Recommendations for following are pending Combined AOX PN Selenium Updated recommendations will have an impact on practices in ICU