1. The 2013 Canadian Critical Care Nutrition Clinical Practice Guidelines: What are the Latest Recommendations? Daren K. Heyland MD Professor of Medicine Queen’s University, Kingston, ON Canada On behalf of the Canadian Critical Care Nutrition Clinical Practice Guidelines Committee 1

2. Disclosures I have received speaker honoraria and/or I have been paid from grants from the following companies: –Nestlé –Fresenius Kabi –Baxter –Abbott 1

3. Learning Objectives Better understand the process by which CPGs are developed Become familiar with recent randomized nutrition trials in critically ill adult patients  Enteral Fish oils  PN and type of Lipids  New Sections Review the updated analyses and recommendations of the Canadian CPGs 1

4. www.criticalcarenutrition.com  Orginally published in 2003  Summarizes 198 trials studying 21283 patients  34 topics 17 recommendations 2005 update 2007 update 2009 update 2013 update

5. Guideline Development Effect size Confidence Intervals Validity Homogeneity Adequacy of control group Biological plausibility Generalizability Safety Feasibility Cost evidenceintegration of values + practice guidelines

6. Language of Recommendations 1

7. Inclusion Criteria Updated to 2013 Randomized controlled trials Critically ill patients (not elective surgery) Clinical Outcomes EMBASE, Medline, Cinhal, reference lists 1

8. New Evidence 2009 ~240 RCTs 34 Topics 17 recommendations 2013 ~275 RCTS 45 Topics 22 recommendations 67 new RCTs across 27 topics!

9. Topic20092013Total Enteral vs Parenteral12214 Early vs. delayed14216 Indirect Calorimetry112 Arginine containing24226 Fish Oils/Borage Oils448 Protein/peptides415 Fibre628 Small Bowel vs. Feeding11415 Probiotics111223 New RCTs per Topic

10. Topic20092013Total Combination EN + PN538 PN Branched Chain A Acids516 Intensive insulin22325 PN Type of lipids549 PN Glutamine171128 Antioxidants16824 PN Selenium11718 New RCTs per topic

11. New Topic# RCTs Intentional Underfeeding: Trophic vs Full Feeds2 Intentional Underfeeding: Hypocaloric EN1 Fish Oils only1 Threshold of GRVs2 Discarding GRVs1 EN: ß Hydroxyl Methyl Butyrate (HMB)1 Early Supplemental PN vs Late1 PN + EN Glutamine1 Optimal glucose control: CHO Restricted Formula + Insulin Therapy 1 Vitamin D1 New Topics (n=10)

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

13. 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 = 4 Rice 2011 Grau-Carmona 2011 Thiella 2011 Elamin 2012 + Pontes Arruda 2011 + Stapleton 2011 (fish oil only)

14. 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

15. OMEGA: 60-Day Mortality P=0.05 P=0.14 Rice et al JAMA Oct 2011 bolus: dilute effect? 50% pts underfed (trophic) protein in placebo include but analyze without

16.  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

17. Clinical Outcomes Grau-Carmona Clin Nutr 2011 Fish Oils: Trend towards lower SOFA scores (NS) First multicentre study to use “usual care” in control group…….no effect on mortality

18.  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 PREVENTION VS. TREATMENT < 50 % patients ventilated Exclude from CPGs

19.  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

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

21. 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

22. Fish oils: effect on mortality removing bolus RCT (n =5) Significant effect, no statistical heterogeneity!

23. 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 Infections (2 RCTs): no effect Reduction in ICU LOS still significant (heterogeneity) Concerns of control group, negative results of large studies 2013 Recommendations Fish Oils/borage oil: Downgraded recommendation to “should be considered” Fish Oils alone: insufficient data

24. Use of PN and type of lipids 1

25. EN + PN No change from 2009 we recommend that PN not be started not be started at the same time as EN. Insufficient evidence in those who are not tolerating EN (case by case) NEJM 2011 Lancet 2012 Early Supplemental PN vs. Late Combined EN + PN Strongly recommend that early PN & high IV glucose not be used in low risk, short ICU stay Insufficient evidence in those who are not tolerating EN (case by case) large multicentre early PN: worse infections, LOS early PN: no diff mortality high glucose loading low risk patients used indirect calorimetry No difference mortality reduced infections day 4-28 + Abrishami 2010 + Chen 2011

26. Lipid Free PN? Recommendation: Based on 2 level 2 studies, in critically ill patients who are not malnourished, are tolerating some EN, or when parenteral nutrition is indicated for short term use (< 10 days), withholding soy bean emulsions should be considered. There are insufficient data to make a recommendation about withholding lipids high in soybean oil in critically ill patients who are malnourished or those requiring PN for long term (> 10 days). Practitioners will have to weigh the safety and benefits of withholding lipids high in soybean oil on an individual case-by-case basis in these latter patient populations. There are no new randomized controlled trials since the 2009 update and hence there are no changes to the recommendation.

27. Vanek VW, et al. Nutr Clin Pract 2012; 27: 150. Soybean Oil ( ω -6) MCT PN without Lipids Olive Oil ( ω -9) Fish Oils ( ω -3)

28. High LCT ω -6 MCT/LCT 50:50 High MUFA Ω -9 High PUFA Ω -3 Mixtures Soybean Oil (SO) SO + Coconut Olive Oil (OO) + SO Fish Oil (FO) SO, FO, Coconut, OO Intralipid ® Lipofundin ® (MCT/LCT) ® ClinOleic ® Omegaven ® SMOF ® Lipoplus ®

30. Study design Randomized clinical, parallel group, controlled trials (RCT) Population Critically ill adult patients (>18 years old) Intervention Parenteral strategies to reduce soybean-oil vs. Ω -6 oil-based LE (LCT) Pre-specified Outcomes Mortality, ICU and Hospital LOS, Infections

31. Manzanares W, et al. Int Care Med 2013 (in press) Ω-6 Sparing Strategies were associated with a reduction in Mortality (RR= 0.83, 95 % CI 0.62, 1.11, P= 0.20, heterogeneity I 2 =0%)

32. Ω-6 Sparing Strategies were associated with a trend towards a reduction in Ventilation Days (WMD -2.57, 95% CI -5.51, 0.37, P=0.09) Manzanares W, et al. Int Care Med 2013 (in press)

33. Ω-6 Reducing Strategies were associated with a trend towards a reduction in ICU LOS (WMD -2.31, 95% CI -5.28, 0.66, P=0.13) Manzanares W, et al. Int Care Med 2013 (in press)

34. LCT plus MCT versus LCT Emulsions No difference in Mortality (RR= 0.84, 95 % CI 0.43, 30 2 31 1.61, P=0.59, heterogeneity I =0%) No difference in ICU LOS (WMD -1.46, 95 % CI -5.77, 2.85, P= 0.51, heterogeneity was present I2= 78%, P=0.03)

35. Ω 9 Oil-based LE versus Soybean Oil-based strategy No difference between the groups in Mortality (RR= 0.90, 95% CI 0.58, 1.39, P=0.62, heterogeneity I2= 0%) Significant reduction in the duration of MV (WMD -6.47, 95% CI -11.41, -1.53, P= 0.01, heterogeneity I2=0%) No effect on ICU LOS (WMD -4.08, 95 % CI - 10.97, 2.81, P=0.25, heterogeneity I2=59%)

36. FO containing lipid emulsions were associated with a trend towards a reduction in mortality RR= 0.71, 95 %CI 0.49-1.04, P= 0.08 0.71 (0.49,1.04) P= 0.08 Manzanares W, et al. JPEN 2013, in press.

37. FO containing emulsions showed a trend towards reduction in the duration of MV days WMD -1.41, 95% CI -3.43, 0.61, P=0.17 P= 0.17 -1.41 (-3.43,0.61) Manzanares W, et al. JPEN 2013, in press.

38. Which Alternative Lipid Emulsion to Use? No head to head trials (and not likely to be) We analyzed our International Nutrition Survey database to evaluate effect of Alt Lipids on outcomes. Analyzed adjusted for key confounding variables. 1 Edmunds, Heyland (in submission)

39. Which Alternative Lipid Emulsion to Use? 1 Edmunds, Heyland (in submission)

40. Which Alternative Lipid Emulsion to Use? 1 Edmunds, Heyland (in submission) CharacteristicLipid-free (n=70) Soybean oil (n=223) MCT oil (n=65) Olive oil (n=74) Fish oil (n=19) papa Age (yrs), mean±SD64.8 ±16.663.5 ±15.961.9 ±16.964.0 ±16.466.2 ±18.30.81 Sex, n (%) Male Female 50 (71.4) 20 (28.6) 135 (60.5) 88 (39.5) 42 (64.6) 23 (35.4) 45 (60.8) 29 (39.2) 9 (47.4) 10 (52.6) 0.31 Body mass index (kg/m 2 ), mean±SD26.1 ±9.828.4 ±8.023.8 ±3.325.6 ±4.727.4 ±6.4<0.001 Admission category, n (%) Medical Emergency surgical Elective Surgical 34 (48.6) 23 (32.9) 13 (18.6) 65 (29.1) 118 (52.9) 40 (17.9) 20 (30.8) 31 (47.7) 14 (21.5) 21 (28.4) 35 (47.3) 18 (24.3) 3 (15.8) 15 (78.9) 1 (5.3) 0.011 APACHE II score, mean±SD23.8 ±9.522.4 ±7.922.7 ±9.321.1 ±8.024.3 ±6.80.30 Mean daily calories from PN, mean±SD1036 ±4281466 ±3721287 ±3131553 ±3881517 ±385<0.001 Mean daily calories from propofol, mean±SD39 ±8928 ±9714 ±3743 ±6513 ±300.005 Mean daily total calories (PN + propofol), mean±SD1084 ±4721499 ±3871306 ±3261625 ±4061532 ±398<0.001

41. Which Alternative Lipid Emulsion to Use? 1 Edmunds, Heyland (in submission) Soybean Fish Oil Olive Oil Lipid Free MCT

42. PN Type of Lipids 2009 Recommendation There are insufficient data to make a recommendation on the type of lipids to be used in critically ill patients receiving parenteral nutrition. 2013 Recommendation: IV lipids that reduce the load of omega-6 fatty acids/soybean oil emulsions should be considered. There are insufficient data on type of soybean reducing lipids

43. New TopicRCTsRecommendation Intentional Underfeeding: Hypocaloric EN 1Insufficient data Threshold of GRVs1Insufficient data (250-500ml) Discarding GRVs1Insufficient data EN: ß Hydroxyl Methyl Butyrate (HMB) 1Insufficient data Optimal glucose control: CHO Restricted Formula + Insulin Therapy 1Insufficient data Vitamin D1Insufficient data Other Topics

44. Summary Many recent RCTs in area of critical care nutrition Careful review of the articles is recommended Recommendations downgraded EN Fish Oils/borage oils PN Glutamine Recommendations upgraded Probiotics Type of PN lipids Recommendations do not change Combined AOX PN Selenium and others New Recommendations PN + EN Glutamine: strongly recommended NOT to be used Early PN vs Delayed PN: Strongly recommend NOT be used Other: Trophic vs full feeds: should NOT be considered Updated recommendations will have an impact on practices in ICU

45. Acknowledgment Co Chair Daren Heyland Leah Gramlich John Drover Brian Jurewitsch Carmen Christman Chelsea Corbett Jan Greenwood Michele McCall Gwynne Macdonald Guiseppe Pagliarello Jim Kutsogiannis John Muscedere Khursheed Jeejeebhoy Courtney Somers-Balota Dominique Garrel Adam Rahman William Manzanares Paul Wischmeyer Rene Stapleton Todd Rice Andrew Davies Emma Ridley Canadian Clinical Practice Guidelines Committee

48. 1