1. Nutrition Therapy in the ICU: The Clock is Ticking! Daren K. Heyland Professor of Medicine Queen’s University, Kingston General Hospital Kingston, ON Canada

2. Case Scenario Mr KT 76 per’d diverticulum Septic shock, ARDS, MODS Day 1- high NG drainage, distended abdomen Day 3- trickle feeds Feeds on and off again for whole first week No PN, no small bowel feeds, no specialized nutrients

3. Case Scenario Prolonged ICU stay, discharged weak and debilitated. Dies on day 43 in hospital from massive PE 114 721 Adequacy of EN

4. To what extent did nutrition therapy (or lack thereof) play a role in this patient’s demise?

5. Conclusions (1) Nutrition is therapy that modulates the underlying disease process Adjunctive Supportive Care Proactive Primary Therapy

6. Conclusions (2) Nutrition therapy impacts clinical outcomes Adjunctive Supportive Care Proactive Primary Therapy

7. Conclusions (3) Timeliness of administration of nutrition therapy matters! Adjunctive Supportive Care Proactive Primary Therapy

8. Conclusions (4) Quantity of nutrition therapy matters! Adjunctive Supportive Care Proactive Primary Therapy

9. Insult infection trauma I/R hypoxemic/ hypotensive Activation of PMN’s = oxidative stress Death organ = failure Pathophysiology of Critical Illness (1) mitochondrial dysfunction Role of GIT Key nutrient deficiencies (e.g. glutamine, selenium) activation of coagulation generation of OFR (ROS + RNOS) endothelial dysfunction elaboration of cytokines, NO, and other mediators cellular = energetic failure Microcirculatory Dysfunction

10. Arginine-supplemented diets?

11. Metabolic Effects of Arginine enteral / parenteral supply L-ArginineL-CitrullineL-Ornithine Polyamine Synthesis Putrescine Spermidine Spermine Hormone release GH IGF Insulin Glucagon Prolactin catecholamines Urea Nitrogenous compounds Nitric oxide Nitrite Nitrate Suchner Brit J Nutrition 2001

12. Mitaka Shock 2003;19: 305 Underlying Pathophysiology Role of Nitric Oxide

13. cNOS cNOS + iNOS Effect of Arginine induced NO formation Harmful Benefitial Arginine / NO availability Optimal NO-Balance - Hemodynamic instability - Immune Suppression - Cytotoxicity - Organe dysfunction - Microcirculation  - Immune augmentation  Suchner Brit J Nutrition 2001

14. Is it plausible that Arginine- supplemented diets may do harm?  Randomized, double blind, placebo- controlled  Beagles  Parenteral L-arginine (+ NAC) vs placebo  Canine model of E. coli peritonitis Kalil Crit Care Med 2006;34:2719

15. Is it plausible that Arginine- supplemented diets may do harm? Arginine administration associated with: Plasma arginine NO products And worse shock, worse organ injury Increased mortality! Kalil Crit Care Med 2006;34:2719 No effect of NAC

16. Is it plausible that Arginine- supplemented diets may do harm?  3 RCTs  3 different products  All describing excess mortality in patients with infection 1) Bower Crit Care Med 1995;23:436 2) Dent, Crit Care Med 2003;30:A17 3) Bertolini Intesive Care Med 2003;29:834

17. Fish Oil supplemented diets?

18. Copyright ©2007 The American Society for Nutrition Mechanisms by which fatty acids can affect immune cell function Wanten, G. J. et al. Am J Clin Nutr 2007;85:1171-1184

19. NFκB Binding CytokinesIL-8TNF-α PGE 1 mRNA

20. CytokinesIL-8TNF-α PGE 1 mRNA NFκB Binding

21. T.T. Pluess 1, D. Hayoz 2, M.M. Berger 1, L. Tappy 3, J.P. Revelly 1, B. Michaeli 1, Y.A. Carpentier 4 and R.L. Chioléro 1

22. 21 patients with sepsis requiring TPN Randomized to recieve PN with an n-3 or n- 6 lipid emulsion for 5 days Dose: 350 ml og s 10% n-3 lipid emulsion (Omegevan) Am J Respir Crit Care Med 2003; 167: 1321

23. TPN with N-3 vs n-6 FAs in severe sepsis. Monocyte membrane FA composition: arachidonic, EPA, DHA Mayer K, Am J Respir Crit Care med 2003; 167: 1321

24. TPN with N-3 vs n-6 FAs in severe sepsis. Ex vivo monocyte cytokine release in response to LPS Mayer AJRCCM 2003; 167: 1321

25. 47 Patients with severe acute pancreatitis Randomized, double blind study of PN N-3 lipid emulsion (omegaven 10%) vs. Soybean emulsion with TPNx 5days Dose of fish oils: 0.15-0.20 g/kg/d Patients comparable at baseline Control group mortality 10%; no deaths in FO group Wang JPEN 2008;32:236

26. Effect of Fish Oils on Inflammatory Cytokines in Pancreatitis Put figure 2 and 3 Wang JPEN 2008;32:236

27. Effect of Enteral Fish Oils/Borage Oils and antioxidants in Critically Ill with ALI RCT of 146 critically ill patients with ALI and BAL+ for WBCs Double-blinded; ITT Experimental: Oxepa® Control: high fat diet Groups well matched at baseline Gadek Crit Care Med 1999;27:1409 After 3-4 days Reduction in AA and increase in EPA in lung and alveolar macrophage Decrease in neutrophils recovered in BAL fluid Improved oxygenation

28. Effect of Enteral Fish Oils/Borage Oils and antioxidants in Critically Ill with ALI RCT of 146 critically ill patients with ALI and BAL+ for WBCs Double-blinded; ITT Experimental: Oxepa® Control: high fat diet Groups well matched at baseline Gadek Crit Care Med 1999;27:1409 P=0.03 P=0.17 P=0.02

29. Overall Effect on Mortality www.criticalcarenutrition.com

30. Glutamine supplementation?

31. Potential Beneficial Effects of Glutamine Fuel for Enterocytes Lymphocytes NuclotideSynthesis Maintenance of Intestinal Mucosal Barrier Maintenance of LymphocyteFunction Preservation of TCA Function Decreased Free Radical availability (Anti-inflammatory action) GlutathioneSynthesis GLNpool Glutamine Therapy Enhanced Heat Shock Protein Shock Protein Anti-catabolic effect Preservation of Muscle mass ReducedTranslocation Enteric Bacteria or Endotoxins Reduction of Infectious complications Inflammatory Cytokine Inflammatory CytokineAttenuation NF-  B NF-  B? Preserved Cellular Energetics- ATP content GLNPool Critical Illness Enhanced insulin sensitivity

32. Induction of Heat Shock Protein Leads to Protein Stabilization Induction Hsp 72 Protein HSP-bound protein stabilized for survival and repair NoInduction Aggregation, denaturation, degradation Stress: e.g. HEAT

33. * IV Glutamine Enhances Serum HSP-70 in Critically Ill Patients ALA-GLN treatment leads to significant enhancement of serum HSP-70 with 7 days of treatment ALA-GLN mediated enhancement of HSP-70 correlates with decreased ICU length of stay and time on ventilator Ziegler Intensive Care Medicine, 31:1079-1086, 2005

34. Mechanism of Glutamine 3 RCTs of enteral glutamine Burns patients –Improved permeability –Decreased endotoxin levels –Reduced GNB infections –Reduced hospital LOS –Reduced mortality Garrell CCM 2003;31:2444, Zhou JPEN 2003 27;241; Peng Burns 2004;30:135

35. Effect of Glutamine: A Systematic Review of the Literature www.criticalcarenutrition.com Infectious Complications

36. Effect of Glutamine: A Systematic Review of the Literature www.criticalcarenutrition.com Mortality

37. Pharmaconutrients Impact Outcomes! www.criticalcarenutrition.com 1 10 1000.1.01 Glutamine Antioxidants Fish/Borage Oils Plus AOX Effect on Mortality Arginine

38. Death Metabolic Shutdown Survivors ↓mt DNA ↓ ATP, ADP, NADPH ↓ Resp chain activity Ultra structural changes ↓ mitochondrial activity Prolonged inflammation NO Endocrine effects cytokine effect Genetic down regulation Tissue hypoxia preserved ATP Recovery of mt DNA Regeneration of mito proteins Underlying Pathophysiology of Critical Illness (2)

39. Mitochondrial Dysfunction is a Time- Dependent Phenonmenon Hypoxia Accelerates Nitric Oxide Inhibition of Complex 1 Activity Nitration of Complex 1 in Macrophages activated with LPS and IFN 21% O2 1% O2 Frost Am J Physio Regul Interg Comp Physio 2005;288:394

40. mitochondria Cell Respiratory chain nucleus nDNA mtDNA Mitochondrial Damage ROS RNS LPS exposure leads to GSH depletion and oxidation of mtDNA within 6-24 hours Levy Shock 2004;21:110 Suliman CV research 2004;279 Potentially Irreversible by 48 hours

41. Heyland JPEN 2007;31:109

42. Effect of Antioxidants on Mitochondrial Function Heyland JPEN 2007;31:109

43. Sakr BJA 2007;98:773 Time Course and Relationship between Plasma Selenium, SIRS, Sepsis, and MOF Plasma selenium level inversely correlated with maximal CRP, PCT, IL-6 Observational study in 60 critically ill patients

44. Smallest Randomized Trial of Selenium in Sepsis  Single center RCT  double-blinded  ITT analysis  40 patients with severe sepsis  Mean APACHE II 18  Primary endpoint: need for RRT  standard nutrition plus 474 ug x 3 days, 316 ug x 3 days; 31.6 ug thereafter vs 31.6 ug/day in control Mishra Clinical Nutrition 2007;26:41-50

45. Smallest Randomized Trial of Selenium in Sepsis Increased selenium levels Increased GSH-Px activity No difference in RRT (5 vs 7 patients) mortality (44% vs 50%) Other clinical outcomes Mishra Clinical Nutrition 2007;26:41-50 *p=<0.006 * * Effect on SOFA scores

46. Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma and subarachnoid hemorrhage patients. CRP levels daily in the Control groups Significant reduction with AOX in Cardiac and Trauma but not SAH Berger Crit Care 2008  RCT  200 patients  IV supplements for 5 days after admission (Se 270 mcg, Zn 30 mg, Vit C 1.1 g, Vit B1 100 mg) with a double loading dose on days 1 and 2 (AOX group), or placebo.  No affect on clinical outcomes

47. Randomized, Prospective Trial of Antioxidant Supplementation in Critically Ill Surgical Patients Nathens Ann Surg 2002;236:814  Surgical ICU patients, mostly trauma  770 randomized; 595 analysed  alpha-tocopherol 1,000 IU (20 mL) q8h per naso- or orogastric tube and 1,000 mg ascorbic acid IV q8h or placebo  Tendency to less pulmonary morbidity and shorter duration of vent days

48. Largest Randomized Trial of Antioxidants  Multicenter RCT in Germany  double-blinded  non-ITT analysis  249 patients with severe sepsis  standard nutrition plus 1000 ug bolus followed by 1000 ug/day or placebo x14 days Greater treatment effect observed in those patients with: supra normal levels vs normal levels of selenium Higher APACHE III More than 3 organ failures Crit Care Med 2007;135:1 p=0.11

49. Effect of Combined Antioxidant Strategies in the Critically Ill Effect on Mortality www.criticalcarenutrition.com

50. Biological Plausibility! Inflammation/oxidative stressMitochondrial dysfunctionOrgan dysfunction Antioxidants

51. Loss of Gut Epithelial Integrity INTESTINAL EPITHELIUM SIRS Bacteria DISTAL ORGAN INJURY (Lung, Kidneys) via thoracic duct Underlying Pathophysiology of Critical Illness (3)

52. Disuse Causes Loss of Functional and Structural Integrity Increased Gut Permeability Characteristics : Time dependent Correlation to disease severity Consequences: Risk of infection Risk of MOFS

53. Enteral Feeding Supports Gastrointestinal Structure and Function Maintenance of gut barrier function Increased secretion of mucus, bile, IgA Maintenance of peristalsis and blood flow Attenuates the stress response Alverdy (CCM 2003;31:598)

54. Effect of Early Enteral Feeding on the Outcome of Critically ill Mechanically Ventilated Medical Patients Retrospective analysis of multiinstitutional database 4049 patients requiring mech vent > 2 days Categorized as “Early EN” if rec’d feeds within 48 hours of admission (n=2537, 63%) Artinian Chest 2006:129;960 P=0.007 P=0.0005 P=0.02

55. Early vs. Delayed EN: Effect on Infectious Complications www.criticalcarenutrition.com

56. Early vs. Delayed EN: Effect on Mortality www.criticalcarenutrition.com

57. Underlying Pathophysiology (4)   Caloric debt associated with:   Longer ICU stay (p=0001)   Days on mechanical ventilation (p=0.0002)   Complications (p=0.0003) 114 721 Adequacy of EN Caloric Debt Villet et al Clin Nutr 2005

58. 2007 International Nutrition Practice Survey Point prevalence survey of nutrition practices in ICU’s around the world conducted Jan. 27, 2007 Enrolled 2772 patients from 158 ICU’s over 5 continents Included ventilated adult patients who remained in ICU >72 hours

59. Hypothesis There is a relationship between amount of energy and protein received and clinical outcomes (mortality and # of days on ventilator) The relationship is influenced by nutritional risk BMI is used to define chronic nutritional risk

60. Relationship Between Increased Calories and 60 day Mortality BMI GroupOdds Ratio 95% Confidence Limits P-value Overall0.760.610.950.014 <200.520.290.950.033 20-<250.620.440.880.007 25-<301.050.751.490.768 30-<351.040.641.680.889 35-<400.360.160.800.012 >=400.630.321.240.180 Legend: Odds of 60-day Mortality per 1000 kcals received per day adjusting for nutrition days, BMI, age, admission category, admission diagnosis and APACHE II score.

61. The Relationship between 60-Day Mortality, Average Daily Total Calories Received and BMI

63. ICU patients are not all created equal…should we expect the impact of nutrition therapy to be the same across all patients?

64. Early Aggressive vs. Early Lower Dose EN  RCT of 82 patients suffering severe head injury  Control:  EN started at 15 ml/hr and advanced per protocol  rate adjusted based on gastric residual 50-150ml  Intervention:  started at full rate  rate adjusted on gastric residual < 200ml  1/3 patients rec’d small bowel feeds Taylor et al Crit Care Med 1999

65. Overview Taylor et al Crit Care Med 1999

66. p=0.08 p=0.02 p=0.046 Early Aggressive vs. Early Lower Dose EN

67.  Cluster RCT of 499 patients at 14 Canadian ICUs  Control:  No intervention  Intervention:  in-service education sessions, reminders, and academic detailing to implement a feeding algorithm  Nutrition practices and Clinical Outcomes in Intervention vs Control:  Calories / day (1264 vs 998 Kcals, p-0,25)  Days of EN per 10 days (6.7 vs. 5.4 days, p=0.042)  Length of hospital stay (25 vs. 35, p=0.003)  Mortality (27% vs. 37%, p=0.058)  No diff in length of ICU stay Martin et al CMAJ 2004

68. Aggressive Gastric Feeding may be a BAD THING!  Observational study of 153 medical/surgical ICU patients receiving EN in stomach  Intolerance= residual volume>500ml, vomiting, or residual volume 150-500x2.  Patients followed for development of VAP (diagnosed invasively) Mentec CCM 2001;29:1955

69.  Incidence of Intolerance= 46%  Statistically associated with worse clinical outcomes!  Risk factors for Intolerance  Sedation  Catecholamines  High residuals before and during EN Aggressive Gastric Feeding may be a BAD THING!

70. Strategies to Maximize the Benefits and Minimize the Risks of EN concentrated feeding formulas feeding protocols motility agents elevation of HOB small bowel feeds weak evidence stronger evidence Canadian CPGs www.criticalcarenutrition.com

71. 4 studies that document increased delivery of protein and calories with small bowel feeding; 2 show no difference One study that documents time goal quicker with small bowel Fewer interruptions with high gastric residuals with small bowel 2 studies document delay in initiating feeds secondary to delay in obtaining small bowel access Small Bowel vs. Gastric Feeding: A meta-analysis Effect on Nutritional Endpoints

72. Effect on VAP www.criticalcarenutrition.com Small Bowel vs. Gastric Feeding: A meta-analysis (9)

73. FRICTIONAL ENTERAL FEEDING TUBE (TIGER TUBE TM ) Flaps to allow peristalsis to pull tube passively forward Sucessful jejunal placement >95%

74. Initial Efficacy and Tolerability of Early Enteral Nutrition with Immediate or Gradual Introduction in Intubated Patients Desachy ICM 2008;34:1054 RCT 100 mechanically ventilated patients (not in shock) 2 Med/surg ICUs All had target 25 kcal/kg All had early EN (within 24 hrs) Immediate goal rate vs gradual ramp up

75. Initial Efficacy and Tolerability of Early Enteral Nutrition with Immediate or Gradual Introduction in Intubated Patients Desachy ICM 2008;34:1054

76. What if you can’t provide adequate nutrition enterally? … to TPN or not to TPN, that is the question!

77. Current practice in nutritional support in septic patients: Results of national, prospective multicenter German Study Point prevalence study 454 ICUs from 310 hospitals in Germany 399 patients septic patients included –Median APACHE II 26 –68% had no GI pathology –46% in shock –Overall mortality 55.2% Elke CCM 2008;36:1762

78. Current practice in nutritional support in septic patients: Results of national, prospective multicenter German Study Point prevalence study 454 ICUs from 310 hospitals in Germany 399 patients septic patients included –Median APACHE II 26 –68% had no GI pathology –46% in shock –Overall mortality 55.2% P=0.005 Multivariate analysis: PN independent predictor for mortality (OR 2.09, 95% CI 1.29-3.37)

79. Prospective Studies of Supplemental PN Effect on Mortality www.criticalcarenutrition.com

80. What if you can’t provide adequate nutrition enterally? … to TPN or not to TPN, that is the question! Maximize EN delivery prior to initiating PN

81. TPN: Mechanisms of Harm  Lipids- immunosuppression  Overfeeding  Hyperglycemia  glutamine deficiency  Atrophy of GIT (lack of enteral stimulation)  Increase in line related sepsis

82. If you are going to use TPN …  Use it late  Low dose EN  No soy bean emulsion lipids  Monitor glucose – avoid hyperglycemia  Supplement with glutamine Consider: Canadian CPGs www.criticalcarenutrition.com

83. Summary Nutrients/Nutritional strategies –Modulate underlying pathphysiological processes –Improve clinical outcomes –Disease processes and treatment effects are time dependent –Quantity of nutrition therapy associated with outcomes, particularly in low and high BMI patients

84. REducing Deaths from OXidative Stress: The REDOXS study A multicenter randomized trial of glutamine and antioxidant supplementation in critical illness

85. 1200 ICU patients Evidence of organ failure R glutamine placebo Concealed Stratified by  site R R antioxidants placebo Factorial 2x2 design placebo antioxidants  Shock REducing Deaths from OXidative Stress: The REDOXS study

86. GroupEnteral Supplement Parenteral Supplement ( Glutamine AOX) (Glutamine AOX) AGlutamine + AOX+Glutamine + Selenium BPlacebo + AOX+Placebo + Selenium CGlutamine + Placebo+Glutamine + Placebo DPlacebo + Placebo+Placebo + Placebo Combined Entered and Parental Nutrients

87. ICU length of stay Nutrition Therapy for Critically ill Patients of the Future Pare n t e r a l Pharmaconutrition Enteral Pharmaconutrition Assement of nutritional risk Measurement of biomarker to determine which pharmaconutrient 1. enteral nutrition ? parenteral nutrition Set of tools to monitor response to nutrition/nutrient therapy

89. Case Scenario Mr KT 76 per’d diverticulum Septic shock, ARDS, MODS Day 1- high NG drainage, distended abdomen Day 3- trickle feeds Feeds on and off again for whole first week No PN, no small bowel feeds, no specialized nutrients

90. Case Scenario Treatment effect function of timeliness –Early goal resuscitation –Appropriate antibiotics –Use of Activated Protein C –Hydrocortisone Early Pharmaconutrients Early EN

91. Elective Surgery Critically Ill GeneralSepticTraumaBurnsAcute Lung Injury ArginineBenefitNo benefitHarmNo benefit GlutamineBenefitPN Beneficial (? receiving EN) …EN Possibly Beneficial … Omega 3 FFA ……………Beneficial Antioxidants…Possible Benefit ………… Population Nutrients Pharmaconutrition: Which Nutrient for Which Population? Canadian Clinical Practice Guidelines JPEN 2003;27:355 www.criticalcarenutrition.com

92. How long do we allow the status quo remain? How many more Mr. KTs have to die before we do something to improve practice? Remember, the clock is ticking…

93. www.criticalcarenutrition.com

94. Questions?