Meta-Analyses, Guideline Development & Implementation Latest Evidence on Nutrition in the ICU: Will it Change Existing Guidelines? June 10th 2011 Rupinder Dhaliwal, RD Clinical Evaluation Research Unit Critical Care Nutrition Kingston ON, Canada 1 Rupinder Dhaliwal

Outline of Session New RCTs in area of critical care nutrition (adult) Updated analyses of Canadian Guidelines Impact on evidentiary basis 1

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

Canadian CPGs 1980-2003 n > 200 RCTs 34 topics 17 recommendations JPEN 2003 1980-2003 n > 200 RCTs 34 topics 17 recommendations 1

2005 update update 2009 update www.criticalcarenutrition.com

Development of Guidelines Validity Homogeneity Safety Feasibility Cost evidence integration of values + practice guidelines 1

Inclusion Criteria Updated to 2011 Randomized controlled trials Critically ill patients (not elective surgery) Clinical Outcomes EMBASE, Medline, Cinhal, reference lists

New RCTs* per Topic (n =51) Meta-Analyses, Guideline Development & Implementation New RCTs* per Topic (n =51) June 10th 2011 Topic # RCTs 2009 # new RCTs Early vs. delayed 14 2 Target dose EN Fish Oils/Borage Oils 5 4 Protein/peptides 1 Fibre 6 Small Bowel vs. Feeding 11 Protocols/GRVs 3 Probiotics 12 7 Supplemental PN PN Type of lipids PN Glutamine 17 8 Antioxidants 16 PN Selenium Total n = 58 of all RCTs * from 2009-2011 Rupinder Dhaliwal

Probiotics 1

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

Lower quality studies > effect vs. higher quality studies Probiotics: effect on infections (n =11) Lower quality studies > effect vs. higher quality studies p = 0.03 2009 update : RR 0.89 [0.68, 1.17] p = 0.4 Petrof et al in submission Critical Care 2012

Meta-Analyses, Guideline Development & Implementation June 10th 2011 Probiotics: effect on VAP (n = 7) Earlier: not enough studies to Petrof et al in submission Critical Care 2012 Rupinder Dhaliwal

Meta-Analyses, Guideline Development & Implementation June 10th 2011 Probiotics: effect on ICU mortality (n = 6) Earlier: No effect 2009 update : RR 0.74 [0.50, 1.09] p = 0.12 Petrof et al in submission Critical Care 2012 Rupinder Dhaliwal

Probiotics with new RCTs stronger signal for reduction in infections higher quality studies do NOT show a reduction in infections significant reduction in VAP still trend towards reduction in ICU mortality 1

Arginine 2009 Recommendation no effect on mortality Based on 22 studies, we recommend arginine and other select nutrients not be used for critically ill patients no effect on mortality no effect on infections 1

Meta-Analyses, Guideline Development & Implementation June 10th 2011 significant reduction in infections p <0.0001 significant shorter HLOS p <0.0001 35 RCTs No effect on mortality Drover et al Am Coll Surg 2011 Rupinder Dhaliwal

(Product enhanced with fish oils +borage oils + antioxidants)* Enteral Fish Oils* ? (Product enhanced with fish oils +borage oils + antioxidants)* 1

Enteral Fish Oils 2009 Recommendation New RCTs = 4 (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

PREVENTION VS. TREATMENT 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 PREVENTION VS. TREATMENT Pontes-Arruda Crit Care 2011;15:R144

Mostly due to reduced Cardio-resp failures PRIMARY OUTCOME: DEVELOPMENT OF SEVERE SEPSIS AND SEPTIC SHOCK Mostly due to reduced Cardio-resp failures Pontes-Arruda Crit Care 2011;15:R144

No difference in survival between the groups Secondary Outcomes Variable Study (n=53) Control (n=53) P Value Use of mechanical ventilation, n (%) Invasive 10 (18.9%) 18 (34%) .03984 Non-invasive 5 (9.4%) 6 (11.3%) NS Number of days using mechanical ventilation 7 (4-12) 15 (9-21) .0033 Number of ICU days 13 (9-18) <.0001 Number of hospital days 9 (6-14) 19 (13-24) No difference in survival between the groups Pontes-Arruda Crit Care 2011;15:R144

Meta-Analyses, Guideline Development & Implementation June 10th 2011 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 Control = ensure plus Grau-Carmona Clin Nutr 2011 Rupinder Dhaliwal

Meta-Analyses, Guideline Development & Implementation Clinical Outcomes June 10th 2011 Fish Oils: Trend towards lower SOFA scores (NS) Non signficant trend for lower SOFa scores Overall: Do not benefit from fish oils in sepsis Grau-Carmona Clin Nutr 2011 Rupinder Dhaliwal

ARDSnet n = 250 “Early Trophic” “Early Full” N-3 + GLA + Antioxidants NIH NHLBI Timing of Feeding “Early Trophic” (10 ml/hr) “Early Full” Fast ramp up S U P L E M N T N-3 + GLA + Antioxidants (Module delivered as bolus bid) n = 250 EDEN OMEGA Trial Factorial design OMEGA and Early enteral (trophic) feeds OMEGA: 21 days, 120 mls X 2/day Stopped for futility No benefit on outcomes or biomarkers of inflammation and may be harmful Control Standard EN (480 cal/ 20 g pro) 24

Meta-Analyses, Guideline Development & Implementation June 10th 2011 OMEGA: 60-Day Mortality P=0.05 P=0.14 P=0.14 Adjusted for baseline demographics differences Rice et al JAMA Oct 2011 Rupinder Dhaliwal

Meta-Analyses, Guideline Development & Implementation June 10th 2011 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 Fish Oils ONLY Bolus Separate from EN Fish oils Stapleton CCM 2011 Rupinder Dhaliwal

Meta-Analyses, Guideline Development & Implementation June 10th 2011 Clinical Outcomes No differences NO diff in biomarkers of inflammation Stapleton CCM 2011 Rupinder Dhaliwal

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

Meta-Analyses, Guideline Development & Implementation June 10th 2011 Fish Oils: Effect on mortality (n = 7) INTERSEPT data not included No effect , statistical heterogeneity! 2009: RR 0.67, 95% CI 0.51, 0.97, p = 0.003 Rupinder Dhaliwal

Fish oils: effect on mortality removing bolus RCTs Meta-Analyses, Guideline Development & Implementation June 10th 2011 Fish oils: effect on mortality removing bolus RCTs Mortality still significant No infections data ICU LOS (significant) and HLOS (significant)..same as before 1 Rupinder Dhaliwal

EN fish oils: with new RCTs Meta-Analyses, Guideline Development & Implementation June 10th 2011 EN fish oils: with new RCTs Effect on mortality disappears when bolus studies are included clinical heterogeneity -studies using bolus fish oils are methodologically different - one RCT does not have GLA, antioxidants statistical heterogeneity with the addition of the bolus studies New RCTs did not report on LOS in mean and SD Rupinder Dhaliwal

Parenteral Fish Oils IV lipid emulsion 1

Meta-Analyses, Guideline Development & Implementation June 10th 2011 Type of Lipids (PN) IV lipid emulsion 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 Fish oil + LCT vs LCT alone or LCT/MCT LCT + MCT vs LCT Olive Oil + LCT vs LCT + MCT LCT vs LCT Fish Oil containing vs LCT/MCT or LCT Olive Oil containing vs LCT/MCT or LCT LCT + MCT vs LCT LCT vs LCT New RCTs = 4 Rupinder Dhaliwal

Meta-Analyses, Guideline Development & Implementation June 10th 2011 p = 0.004 N = 25 septic pts PN + Fish Oil vs. PN + soybean oil Barbosa Crit Care 2010 Rupinder Dhaliwal

Meta-Analyses, Guideline Development & Implementation June 10th 2011 N = 56 patients with SAP, China PN with Fish Oils (+ LCT) vs PN (LCT) X 5 days Fish Oils improved plasma IL-10 levels, decreased HLA= anti-inflammatory No effect on clinical outcomes Sabater: safe Wang: pilot study, no differences in outcomes Wang Inflammation 2009 Rupinder Dhaliwal

Supplementation with Fish Oils 100 mls/day X 5 d vs. Placebo (saline) N= 28 patients with Severe Sepsis, Taiwan Supplementation with Fish Oils 100 mls/day X 5 d vs. Placebo (saline) Reduction in APACHE 3 score: improved more in Fish oil group Days 3, 5 & 7 (p =0.03-0.004) Khor Asian J Surg 2011

Meta-Analyses, Guideline Development & Implementation June 10th 2011 Procalcitonin levels Procalcitonin levels are a marker of inflammatory response No difference in hospital or length of stay between the groups PCT levels decrased significanty suggesting that fish oils attenuate the infl process. Khor Asian J Surg 2011 Rupinder Dhaliwal

Supplementation with Fish Oils + EN vs. EN alone X 14 days Oxygenation N = 61 patients with ARDS, India Supplementation with Fish Oils + EN vs. EN alone X 14 days Oxygenation P/F ratio: no differences worsening in P/F ratio: higher in control group (p=0.0004) Mortality: trend towards lower in Fish Oil group (p = 0.10) Ventilation, ICU LOS: no difference Gupta Ind J Crit Care Med 2011

Meta-Analyses, Guideline Development & Implementation June 10th 2011 Fish Oil vs LCT + MCT: Updated Effect on mortality (n = 7) Was no effect, now there is 2009: RR 0.76, [0.46, 1.26], p = 0.29 1 Rupinder Dhaliwal

Fish Oil vs LCT or LCT + MCT: Effect on infections (n = 3) Meta-Analyses, Guideline Development & Implementation June 10th 2011 Fish Oil vs LCT or LCT + MCT: Effect on infections (n = 3) No changes as infections not reported 2009: RR 0.77 [0.39, 1.49], p = 0.43 1 Rupinder Dhaliwal

PN lipids: with new RCTs Other lipids: no changes fish oils: studies with different designs 2 studies of lipids in PN 2 studies of supplemental fish oils fish oils: signal for reduction in mortality fish oils: still no effect on infections 1

Glutamine supplementation? Meta-Analyses, Guideline Development & Implementation June 10th 2011 Glutamine supplementation? Low plasma levels at icu admission = mortality 1 Rupinder Dhaliwal

Meta-Analyses, Guideline Development & Implementation June 10th 2011 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 2 Chinese RCTs Chinese RCTs New RCTs = 2 Rupinder Dhaliwal

Meta-Analyses, Guideline Development & Implementation June 10th 2011 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 2 Chinese RCTs Grau 2011 Andrews 2011 Wernerman 2011 Eroglu 2009 Perez Barcena 2010 + possibly 3 Chinese RCTs New RCTs = 5 Rupinder Dhaliwal

Randomized 2.6 days after admission to ICU 10 centres in Scotland 502 Patients expected to be in ICU for at least 48h and required PN meet at least half their requirements 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 Selenium 500μg/d Both Neither Median duration of study PN was 4-5 days Andrews BMJ 2011:342

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

The SIGNET Trial – Questions! Right patient population? Only about half getting PN at time of randomization Timing of intervention? Started too late (2.6 days plus time to get PN running) Inadequate exposure to intervention? Too small of dose Too short of duration (4-5 days)

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

P=0.10 P=0.03 Grau CCM 2011; 39

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

PN glutamine group: lower mortality PP p = 0.046 ITT p = 0.098 Wernerman Acta Anesthesiology 2011

Meta-Analyses, Guideline Development & Implementation June 10th 2011 Ahmet Eroglu Anesthesia Anal 2009 Critical Care 2010 Eroglu Turkey ~ 40 patients.no diff Perez-Barcena Spaon 40 patients, no diff Rupinder Dhaliwal

PN GLN: mortality revised (n = 20) 2009 RR 0.71 [0.55, 0.52] p = 0.008

PN GLN: infections revised (n = 12) 2009 RR 0.76 (0.62, 0.93) p = 0.008

Meta-Analyses, Guideline Development & Implementation June 10th 2011 PN GLN with new RCTs less effect on mortality, still a trend less effect on infections, still significant HLOS: no changes 1 Rupinder Dhaliwal

Awaiting results

REDOXS Training: RD & Pharmacy The REDOXS© Study REducing Deaths from OXidative Stress Study Chair Dr. Daren Heyland Enrolment completed, n =1200 Results expected Summer 2011 November 2008 November 2008 57

Antioxidant supplementation Parenteral Selenium 1

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 New RCTs = 5

Meta-Analyses, Guideline Development & Implementation June 10th 2011 Randomized, open-label, single-centre clinical trial 150 patients with SIRS/sepsis and a SOFA score of >5 Patients in the Se group received 1,000 ug on day 1 followed by 500 ug/day on days 2–14 Administered daily over 30 mins Patients in both groups received a standard Se dose (75 ug/day) No differences in mortality Lower mortality in patients with a higher APACHE p =0.10 Rupinder Dhaliwal

Phase II study building on previous dosing work 35 Patients with SIRS and APACHE II >15 Randomized within 24 hrs of admission Received either placebo or IV Se as a bolus-loading dose of 2,000 ug followed by continuous infusion of 1,600 ug/ day for 10 days. Lower VAP (p =0.04) Lower SOFA at day 10 (p=0.01)

The SIGNET Trial – RESULTS Effect of Selenium Confirmed infections within 14 days Mortality P=0.12 P=0.02 No significant differences

Meta-Analyses, Guideline Development & Implementation June 10th 2011 Scneider, Germany, n =58 : Intestamin: GLN + Se, no difference El Attar, Egypt, n = 80, Se, Mg, Zinc: reduction in ventilation Rupinder Dhaliwal

Manazares et al in submission 2012 AOX combined mortality, n =20 2009 0.76 RR [0.64, 0.91], p = 0.002 Manazares et al in submission 2012

Manazares et al in submission 2012 AOX combined Infections, n=10 2009 RR 0.94 [0.75, 1.17], p = 0.56 Manazares et al in submission 2012

Meta-Analyses, Guideline Development & Implementation June 10th 2011 AOX: did decrease vent days No effect on LOS Rupinder Dhaliwal

Antioxidants with new RCTs still significant effect on reduction on mortality stronger reduction on infections reduction stronger signal in sicker patients selenium associated with a trend towards lower mortality & infections 1

Conclusion Many recent RCTs in area of critical care nutrition Careful review of the articles is recommended Recommendations for following not expected to change: Arginine EN glutamine PN glutamine IV fish oils Recommendations for following may be upgraded: Probiotics and AOX Recommendations for the following pending discussion EN Fish Oils Other Societies for critical care: harmonize the evidence