Copyright 2011 Nestlé. All rights reserved.

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1 Sponsor Disclosure: This presentation has been prepared and sponsored by Nestlé HealthCare Nutrition, Inc. The material herein is for educational purposes only and is not intended as a substitute for medical advice. Reproduction of these materials is prohibited. This presentation is dated November, 2011 and the information contained herein may only be accurate as of such date Juan B. Ochoa MD, FACS Professor of Surgery and Critical Care University of Pittsburgh- on leave Medical and Scientific Director, Nestlé HealthCare Nutrition, NestléHealthScience Copyright 2011 Nestlé. All rights reserved. 1

2 Objectives: 1) Review the evidence demonstrating positive patient outcomes associated with the use of immunonutrition formulas 2) Describe the potential health economic benefit of surgical immunonutrition in GI cancer surgery patients 2

3 Post operative infections are an increasing burden to healthcare providers Infections are the most frequent cause of morbidity after surgery Up to 54% of all HAIs (Healthcare-Associated Infections) occur in high risk surgical populations. Dept of Health and Human Services (HHS) has identified the following infections account for approximately 75% of HAIs in acute care hospitals: 34% urinary tract infections 17% surgical site infections 14% bloodstream infections 13% pneumonia Surgical site infections costing the system $ billion Klevens RM et al. Public Health Rep 2007, Richards MJ et al. Inf Cont Hosp Epid 2000 Scott RD. CDC

4 Post-Surgical Infections as a measure of Quality and Reimbursement CMS Pay for performance changes Certain Hospital Acquired Conditions (HACs)- no additional reimbursement (i.e. catheter associated UTI; certain SSI) Effective Oct 2012, incentive/disincentive for all CMS reimbursement to be tied to Clinical Quality Indicators Healthcare-Associated Infections (HAIs) Evidence based Quality Measures i.e. Surgical Care Improvement Hospital specific data to be available on Hospital Compare website In line with health care reform objectives, HHS Issued Action plan to prevent HAIs Most common adverse event ownloads/hacfactsheet.pdf ; HHS 2009; CMS 2011; AHRQ HCUP data

5 Reducing Risk of Infection after Surgery PATHOGEN NUTRITION ENVIRONMENT HOST 5

6 Simple interventions in surgical patients significantly improve outcomes Antibiotics within 1 hour of surgery Not shaving Glucose control Avoid hypothermia Nutrition Intervention Nutrition intervention is often overlooked SCIP Measures SCIP (Surgical Care Improvement Project) Colorado Foundation for Medical Care. Accessed October 26,

7 Surgery patients are more susceptible to Infection due to Arginine Deficiency T-Cell Dysfunction Risk of INFECTION Immunonutrition restores plasma arginine levels to support decreased risk of infections Arginine Deficiency Popovich 2006; McClave 2009; Zhu

8 Evidence Based Outcomes: Waitzberg Meta-Analysis 17 randomized trials in elective GI cancer, H/N cancer and cardiac surgical patients n= 2305 Compared the same immunonutrition formula with control nutrition intervention Examined relationship between pre-, peri- and postoperative specialized nutrition support and outcomes: Post-op infectious complications reduced by 39%-61% (p<0.0001) Anastomotic leaks: by 44% (p=0.004) Pneumonia: by 47% (p<0.0001) Wound infections: by 35-40% (p=0.005) Abdominal abscesses: by 54% (p=0.001) UTI: by 47% (p=0.011) Waitzberg et al, WJS Hospital LOS: 2 days less on average (p<0.0001) 8

9 Waitzberg Meta-Analysis Take-Aways Immunonutrition supplementation appears warranted in major elective surgical patients as part of a proactive approach to infection control Clinical benefit shown for pre-, post- and peri-operative use of an immunonutrition formula containing a blend of: L-Arginine Omega-3 fatty acids (fish oil) Dietary nucleotides Where preoperative use not possible, early postoperative immunonutrition supplementation can improve outcomes beyond standard nutrition Waitzberg et al. WJS

10 Evidence Based Outcomes: Marik Meta-Analysis Summary of Studies Included in Meta-Analysis Timing of Immunonutrition Author Year Setting Formula Immunonutrients Pre-op (n=1) Xu 2006 GI malignancy A N 60 Blind Number of Patients Daly 1992 GI malignancy A N 85 Daly 1995 GI malignancy A Y 60 Kenler 1996 GI malignancy B Y GI malignancy A Y 40 Schilling 1996 GI malignancy A N 28 Gianotti 1997 GI malignancy A N 174 Senkal 1997 GI malignancy A Y 154 Formulas: A- arg/n3/nucleotides B- n3 alone C- arg alone D- arg-n3 Post-op (n=15) 1998 GI malignancy A Y 110 Snyderman 1999 H&N malignancy A Y 129 Di Carlo 1999 GI malignancy A N 68 De Luis 2002 H&N malignancy C Y 47 Jiang 2004 GI surgery D Y 120 Farreras 2005 GI malignancy A Y 60 Lobo 2006 GI malignancy D Y 108 (n= 1918) Peri-op (n=5) Casas-Rodera 2008 H&N malignancy C Y GI malignancy A Y 206 Senkal 1999 GI malignancy A Y 154 Tepaske 2001 Cardiac surgery A Y GI malignancy A Y 100 Helminen 2007 GI surgery A Y 100 Marik PE, Zaloga GP. JPEN. 2010;34:

11 Immunonutrition vs. Control Formulas High-Risk Patients Undergoing Elective Surgery who Received Immunonutrition Formulas Risk of Hospital Acquired Infections Significantly Reduced by 38% - 61% OR 0.49; 95% CI, , P< vs. control formula Wound Complications Significantly Reduced by 9% - 60% OR 0.60; 95% CI, , P=0.02 vs. control formula Hospital Length of Stay Reduced on Average by 3 Days days; 95% CI, to days, P< vs. control formula Benefits of immunonutrition required use of formulas containing both Arginine and Fish oil Pre-op use starting at least 5 days prior to surgery and continuing post-op when feasible advised Marik PE, Zaloga GP. JPEN. 2010;34:

12 Evidence Based Outcomes: Drover Meta-Analysis 35 studies in major elective surgery (n= 3438) n= /35 studies in elective GI surgery Evaluated pre-, peri- and post-operative use of arginine-supplemented diets (immunonutrition) on outcomes: Primary outcome Infectious complications reduced by 41% (p< ) Secondary outcomes Hospital LOS reduced WMD 2.38 days (p< ) Mortality: No change Various sub-analyses Drover et al. J Am College Surgeons Mar

13 Sub-analyses of Arginine-Supplemented (Immunonutrition) Formulas on Infection Figure 4. Results of Subgroup Analyses examining the Effect of Arginine Supplemented Diets on Infection Same benefit shown for GI surgery vs non GI surgery Same benefit shown for Upper and Lower GI surgeries Arg-n3-nucleotide formula showed significantly more benefit than other arginine supplemented formulas (p<0.0001) Peri-operative use showed greatest benefit (p= 0.03) GI studies (21) Non GI studies (7) Lower GI studies (1) Upper GI studies (16) Lower & Upper GI studies (4) Arg+FO+nucleo (21) Other (7) Pre Op studies (6) Peri Op studies (9) Post Op studies (15) Infections Overall P=0.28 P=0.06 P< P=0.03 P< RR Arginine Beneficial Arginine Harmful Drover et al. J Am Coll Surgeons Mar 2011 Number in parenthesis indicates number of studies 13

14 Sub-analyses of Arginine supplemented diets on LOS Figure 5. Results of Subgroup Analyses examining the Effect of Arginine Supplemented Diets on Length of Stay GI studies (21) P= Significantly more benefit shown for: Non GI surgery (p=0.0007) Non GI studies (8) Lower GI studies (2) Upper GI studies (14) Lower & Upper GI studies (5) P=0.004 Upper GI Surgery (p=0.004) Use of a formula containing Arg-n3-nucleotides (p<0.0001) Peri-operative use (p=0.001) Arg+FO+nucleo (21) Other (8) Pre Op studies (6) Peri Op studies (11) Post Op studies (14) P< P=0.001 Number in parenthesis indicates number of studies Length of Stay Overall P< Drover et al. J Am Coll Surgeons Mar 2011 WMD Weighted Mean Difference (in days) 14

15 Immunonutrition: Peri-operative use in Malnourished Patients Study Design: Prospective, randomized, placebo-controlled, double-blind clinical trial 150 malnourished patients (weight loss 10%) with malignancy of the GI tract 3 Groups: Control std TF post-op Pre-op IMF (7 days); std TF post-op Peri-Op IMF (before and after surgery) Primary endpoints: Rate of post-operative complications Hospital LOS Braga, 2002 Arch Surg 15

16 Perioperative Immunonutrition: Malnourished Patients- Results Results: Reduced post operative complication rates: Pre- and peri-op IMF 18% Pre- IMF 28% Control 42% Shorter hospital LOS by 2.7 days (pre- or peri-op IMF) Braga, 2002 Arch Surg 16

17 Perioperative Immunonutrition Well Nourished Patients 45%-50% reduction in infections Shorter LOS in both study groups p=0.006 p=0.008 % Infections LOS (days) Pre-Op Peri-Op Control Gianotti 2002 Gastroenterology 17

18 Immunonutrition in GI Cancers Klek et al randomized 305 patients after 14 days of preoperative parenteral nutrition to a postop immuno-modulating diet or standard diet Immuno-modulating diet included arginine, omega-3 fatty and glutamine Surgeries included gastric and pancreatic resections Klek et al, Clin Nutrition 30; :

19 Immunonutrition in GI Cancers Infectious complications Length of Stay (Days) Mortality Standard nutrition (n=153) Immunomodulatory (n=152) 39.2% % 28.3% % p value Klek et al, Clin Nutrition 30; :

20 Immunonutrition and Head/Neck Cancer Surgery- Infection Rates Incidence of postoperative infectious complications significantly reduced in the immunonutrition group (p = 0.04 actual therapy analysis) LOS did not differ between treatment groups, however ICU days on average were shorter in the immunonutrition group (7 vs. 10 days; p = 0.09) % Infectious Complications IMF Standard 5 0 Snyderman CH et al. Laryngoscope

21 Surgical Immunonutrition reduces risk of infectious complications, but. Is surgical immunonutrition cost-effective? How about cost-saving? saving? 21

22 Health Economics of Immunonutrition Previous studies Braga M et al. Nutrition 2005 Strickland A et al. JPEN 2005 Farber MS et al. JPEN 2005 Senkal M et al. CCM 1997 Shulkin DJ et al. Arch Surg

23 Options for calculation methods 1. A database evaluation of the cost of complications on cost of stay 2. A database evaluation of cost per stay on LOS (cost/day) 3. Actual costs in a given institution 23

24 Studying cost/benefit of Surgical Immunonutrition Intervention Focus on the most studied population: GI Cancer Surgery Select outcomes associated with the most studied combination of immunonutrients to reduce variables Utilize a large, reputable US database to identify costs associated with infectious complications and LOS in GI cancer surgery 24

25 Peri-operative Immunonutrition Health Economic Model Cost for GI Patients without Immunonutrition Part I: Outcomes of Peri-operative Immunonutritio n Part II: US Hospital Cost Data Cost for GI Patients with Immunonutrition Model that Estimates Potential Hospital Cost Savings for GI Cancer Surgery Mauskopf J et al. ESPEN 2011; Submitted to JAMA 25

26 Part I: Evidence Based Outcomes from Waitzberg- Reduction in Risk of Complications % Reduction in Risk IMF Control 53% Reduction in Risk with Immunonutrition 39-61% (p<0.0001)) /17 randomized trials in GI Cancer surgery (n= 2083) Peri-operative application (n=889) RR= 0.47 One immunonutrition formula (arginine, n-3 fatty acids and nucleotides) vs. control -70 Waitzberg DL, et al. WJS

27 GI Cancer Surgery- Types Upper GI Surgery Esophagus Stomach Pancreas Lower GI Surgery Small intestine (rare) Colon 27

28 Peri-operative Immunonutrition Health Economic Model Assumptions All outcomes from Waitzberg are based on studies that utilized an oral supplement and/or tube feeding product that contained a blend of three immunonutrients: Arginine Omega-3 fatty acids from fish oil Nucleotides Peri-operative immunonutrition formula protocol: Preoperative oral supplement- 750 ml per day x 5 days Postoperative tube feeding kcal per day x 5 days 28

29 Peri-operative Immunonutrition Health Economic Model Two separate methods of estimating Cost Savings are utilized: 1. LOS Method- Reduction in cost associated with a % reduction in the LOS observed in Waitzberg (GI cancer studies) Dependent on Cost/Day Calculation from HCUP 2. Complication Method- Reduction in cost associated with a % reduction in the occurrence of post-surgical complications observed in Waitzberg (GI cancer studies) Dependent on Cost/Stay Calculation from HCUP 29

30 Part II: US Hospital Cost Data Healthcare Cost and Utilization Project (HCUP) Largest all payer database in US 8 million hospital stays Representative of all US hospital stays Charges converted to costs using facility specific cost-to-charge ratios provided by HCUP 2008 costs adjusted to 2010 dollars Estimated average cost per day for GI cancer surgery patients (n=19,357): $2,948 HCUP Nationwide Inpatient Sample (NIS). Healthcare Cost and Utilization Project (HCUP) Agency for Healthcare Research and Quality, Rockville, MD. 30

31 Peri-Op Immunonutrition* Estimated Potential Savings Based on Hospital Length of Stay and Cost per Day Inputs Clinical Outcomes Hospital length of stay with immunonutrition Hospital length of stay without immunonutrition 13.3 days 15.5 days Waitzberg et al 2006 Inputs Hospital Costs Hospital cost per day for those with GI cancer surgery $ 2,948 HCUP *Containing arginine, n-3 fatty acids and nucleotides 31

32 Peri-Op Immunonutrition* Estimated Potential Savings Based on Hospital Length of Stay and Cost per Day Outputs Without With immunonutrition immunonutrition* Difference Hospital average length of stay (-14%) Mean total hospital cost / stay $45,635 $39,219 -$6,416 Estimated number of patients 100 Estimated potential cost savings per patient $6,416** Estimated potential cost savings per 100 patients $641,600** *Containing arginine, n-3 fatty acids and nucleotides. Cost of immunonutrition not included. **Estimated potential cost savings included in this health economics model are for illustrative purposes only and are not intended to guarantee any specific reductions in cost at a 32 particular facility.

33 Peri-operative Immunonutrition Health Economic Model Two separate methods of estimating Cost Savings are utilized: 1. LOS Method- Reduction in cost associated with a % reduction in the LOS observed in Waitzberg (GI cancer studies) Dependent on Cost/Day Calculation from HCUP 2. Complication Method- Reduction in cost associated with a % reduction in the occurrence of post-surgical complications observed in Waitzberg (GI cancer studies) Dependent on Cost/Stay Calculation from HCUP 33

34 Part II: US Hospital Cost Data Healthcare Cost and Utilization Project (HCUP) Estimated average cost per hospital stay for GI cancer surgery Without infectious complications: $19,629 (n= 14,042 ) With infectious complications: $41,119 (n= 5,315 ) 20.8% with infectious complications in HCUP Waitzberg was 25%-31% HCUP Nationwide Inpatient Sample (NIS). Healthcare Cost and Utilization Project (HCUP) Agency for Healthcare Research and Quality, Rockville, MD. 34

35 Types of Complications Anastomotic leaks Pneumonia Wound infections Abdominal abscesses UTI Waitzberg DL, et al. WJS

36 Peri-operative Immunonutrition* Estimated Potential Savings Based on Reduction in Risk of Complications** Clinical Outcomes (Waitzberg et al 2006) Base complication rate 31.32% Reduction in risk of complications with immunonutrition 53% Calculated Costs Hospital cost/stay with complications $41,119 Hospital cost/stay with complications $19,629 *Containing arginine, n-3 fatty acids and nucleotides; Cost of immunonutrition not included. **Estimated potential cost savings included in this health economics model are for illustrative purposes only and are not intended to guarantee any specific reductions in cost at a particular facility. 36

37 Peri-operative Immunonutrition* Estimated Potential Savings Based on Reduction in Risk of Complications** Results: Cost per stay with immunonutrition $22,790 Cost per stay without immunonutrition $26,360 Potential cost savings per patient stay $3570 Potential cost savings per 100 patient stays $357,000 *Containing arginine, n-3 fatty acids and nucleotides;cost of immunonutrition not included. **Estimated potential cost savings included in this health economics model are for illustrative purposes only and are not intended to guarantee any specific reductions in cost at a particular facility. 37

38 Sensitivity Analysis- Complications Method* Estimated Potential Cost Savings/Patient** Potential Savings ($) per patient stay $342 $570 $1710 $1140 $2371 Base Complication Rate (%) *Containing arginine, n-3 fatty acids and nucleotides;cost of immunonutrition not included. **Estimated potential cost savings included in this health economics model are for illustrative purposes only and are not intended to guarantee any specific reductions in cost at a particular facility. 38

39 Potential Estimated Cost Savings The LOS calculation projects a larger savings than the Complications calculation Those with complications in the immunonutrition group had complications that were less severe allowing a shorter LOS? 39

40 Health Economic Take-Aways Use of surgical nutrition intervention (containing arginine, n-3 fatty acids and nucleotides) has been shown to help reduce hospital LOS and the rate of infectious complications following GI cancer surgery The National Inpatient Sample of US hospitalizations (HCUP data base), allows us to take the difference in clinical outcome and estimate potential cost savings for US Hospitals associated with this type of surgical immunonutrition protocol in GI cancer surgery 40

41 WHAT IF surgical nutrition was Standard of Care for GI surgery in the US? HCUP Database: Complete Records 95,198 weighted cases GI cancer surg/year X $2,371 potential estimated savings/stay = $ Mn CDC Cases 3.2 million cases GI surgery/year X $2,371 potential estimated savings/stay = $7.6 Bn HE models in cardiac and head/neck surgery have not yet been explored CDC Nat Health Statistics. 29; 2010 (data from 2007) HCUP

42 Conclusions Surgical immunonutrition given peri-operatively supports Decreased infections Decreased complications Saving of healthcare costs Demonstrated in GI cancer surgery patients Surgical immunonutrition needs to be standard of care Call to action 42

43 Surgical Immunonutrition Protocol - A New Standard of Care 5 Days Preoperatively At least 5 Days Postoperatively if feasible 500 ml 1000 ml IMF formula/day At least 1000 kcal IMF formula/day (meet at least 50-65% of needs) Waitzburg 2006; Marik 2010; McClave 2009; August 2009; Drover 2011 IMF= Immunonutrition Formula 43

44 Acknowledgements RTI Health Solutions Dr. Josephine Mauskopf PhD Health Economist Ms. Hélène Chevrou Séverac NestléHealthScience, Global Health Economics 44

45 Mary Miranowski RD, CNSC Medical Scientific Liaison Medical Affairs Nestlé HealthCare Nutrition, NestléHealthScience Sponsor Disclosure: This presentation has been prepared and sponsored by Nestlé HealthCare Nutrition, Inc. The material herein is for educational purposes only and is not intended as a substitute for medical advice. Reproduction or distribution of these materials is prohibited. Copyright 2011 Nestlé. All rights reserved. 45

46 Objectives: 1) Differentiate immunonutrition from standard nutrition formulations 2) Describe important tools to assist implementation of an evidence-based protocol for surgical immunonutrition. 46

47 Enteral Formulas Standard, polymeric Specific Disease or Conditions GI Dysfunction Diabetes/Glucose Intolerance Hepatic Failure Immunonutrition- Surgery and Critical Care Pulmonary Failure Renal Failure Wound Healing A.S.P.E.N. Core Curriculum

48 Standard Polymeric Enteral Formulas In General: 14%-18% protein, in whole protein form Corn syrup solids are the primary source of CHO LCT is the predominant fat source Macro and micronutrients to meet DRI Examples: Tube feedings: Isosource 1.5, Jevity Oral supplements: Boost, Ensure A.S.P.E.N. Core Curriculum

49 Immunonutrition Enteral Formulas In General: High protein (20%-25%; protein may be hydrolyzed) Maltodextrin +/or hydrolyzed cornstarch primary sources of carbohydrate Usually contains both MCT and LCT May contain a variety of supplementary nutrients shown to have effects on immune function and/or inflammation L-arginine, L-glutamine n3 fatty acids: EPA, DHA n6:n3 fatty acid ratio of 2:1 Nucleotides Antioxidant vitamins/minerals Examples: Impact, Pivot 1.5 Cal, Peptamen Bariatric, Perative 49

50 Immunonutrition- Immune Modulating Nutrients E1: IMMUNE MODULATING ENTERAL FORMULATIONS CONTAINING INGREDIENTS SUCH AS: Arginine Glutamine Nucleic acid (Nucleotides) Omega-3 fatty acids Antioxidants SHOULD BE USED FOR APPROPRIATE PATIENT POPULATIONS: Major elective surgery, trauma, burns, head/neck cancer Critically ill patients on mechanical ventilation WITH CAUTION IN PATIENTS WITH SEVERE SEPSIS Surgical ICU (Grade A) Medical ICU (Grade B) SCCM/ASPEN, McClave S JPEN

51 Critical Care Nutrition Guidelines- Grades Grade of Recommendation Level of Evidence A At least two LEVEL I investigations I Large, randomized trials with clearcut results B One LEVEL I investigation II Small, randomized trials with uncertain results C LEVEL II investigations only III Non-randomized, contemporaneous controls D At least two LEVEL III investigations IV Non-randomized historical controls E LEVEL IV or LEVEL V evidence V Case series, uncontrolled studies and expert opinion SCCM/ASPEN, JPEN

52 Guidelines for the Surgery Patient A.S.P.E.N. Cancer Care Nutrition Guidelines Guideline 10: IMMUNE ENHANCING ENTERAL FORMULATIONS CONTAINING MIXTURES OF: Arginine Nucleic acids (Nucleotides) Essential fatty acids (n-3) GRADE A May be beneficial in Malnourished Patients Undergoing Major Cancer Operations August DA, Huhmann MB JPEN

53 Guidelines for the Surgery Patient E.S.P.E.N. Surgery Nutrition Guidelines Guideline 4.2.3: USE ENTERAL NUTRITION WITH IMMUNO-MODULATING SUBSTRATES: Arginine, Nucleic acids (Nucleotides), and Omega-3 fatty acids GRADE A Peri-operatively and independent of nutritional risk for those patients: Undergoing major neck surgery for cancer Undergoing major abdominal cancer surgery After severe trauma Weimann A et al Clin Nutr

54 Immunonutrients, NOT Soup Du Jour Arginine Glutamine Omega-3 Fatty Acids Nucleotides Antioxidants 54

55 Antioxidants Glutathione Vitamin C Vitamin E Vitamin A β-carotene Selenium Zinc Oxidative Free Radicals Damage to DNA Mutation of tumor oncogenes Protein/cell damage Lipid peroxidation (change of cell membrane fluidity) Vs. Antioxidants Suppress the formation of free radicals Scavenge free O 2 species Inhibit lipid peroxidation Repair oxidative damage 55

56 Glutamine Major metabolic fuel for rapidly replicating cells (i.e. GI mucosa, immune cells) Maintains gut mucosal integrity and reduces bacterial overgrowth Multiple physiologic roles (nitrogen shuttle, visceral protein synthesis, precursor for glutathione, ammonia production) Improved clinical outcome Hospital and ICU LOS (Mixed ICU patients) Mortality (Burn Patients) ASPEN Nutrition Support Practice Manual, 2005; Schloerb JPEN 2001;25:S3-7; 2009 SCCM/ASPEN guidelines 56

57 Glutamine continued No ready to use immunonutrition diets in the US contain supplementary glutamine; must be added as a bolus g/kg/d glutamine powder, mixed with water and given in divided doses Glutamine may be converted to Arginine via a Citrulline pathway Alanine Glutamine Citrulline Arginine Glutamic Acid 2009 SCCM/ASPEN guidelines ; Ligthart-Melis GC; Am J Clin Nutr

58 Immunonutrition in GI Cancers Klek et al randomized 214 patients to standard or immunomodulatory enteral and parenteral nutrition Nutritional supplements included glutamine and omega-3 fatty acids All nutrition was delivered after upper gastrointestinal surgery Surgeries included esophageal, gastric, pancreatic and colorectal Klek et al, Ann Surg 248; :

59 Immunonutrition in GI Cancers Standard nutrition (n=102) Immunonutrition (n=103) Infectious complications Length of Stay (Days) 27% % 12.5 p value NS NS Klek et al, Ann Surg 248; :

60 Immunonutrition in GI Cancers Klek et al randomized 305 patients after 14 days of preoperative parenteral nutrition to a postop immuno-modulating diet or standard diet Immuno-modulating diet included arginine, omega-3 fatty and glutamine Surgeries included gastric and pancreatic resections Klek et al, Clin Nutrition 30; :

61 Immunonutrition in GI Cancers Infectious complications Length of Stay (Days) Mortality Standard nutrition (n=153) Immunonutrition (n=152) 39.2% % 28.3% % p value Klek et al, Clin Nutrition 30; :

62 Arginine A nitrogen- rich amino acid; indispensable in stressed states Supports T-lymphocyte replication and growth to support immune function Promotes wound management and reduces the risk of infectious complications Martindale RG et al. Crit Care Med 2009;37(5). 62

63 Arginine Pathways Major Elective Surgery and Trauma T-cell Proliferation Collagen Production Decreased Infection Risk Tissue Repair Ochoa et al. NCP

64 Surgery patients are more susceptible to Infection due to Arginine Deficiency T-Cell Dysfunction Risk of INFECTION Immunonutrition restores plasma arginine levels to support decreased risk of infections Arginine Deficiency Popovich 2006; McClave 2009; Zhu

65 How Does Physical Injury (Surgery/Trauma) Affect the Immune System? Cytokine activation of ASE-1 MDSC Arginine Deficiency Syndrome ASE-1 Arginine MDSC= Myeloid Derived Suppressor Cells ASE-1= Arginase Popovich, Zeh, Ochoa

66 Myeloid Derived Suppressor Cells (MDSCs) Immature cells made in the bone marrow May include: Macrophages Granulocytes Immature dendritic cells ARG 1 Regulate arginine availability Create an Arginine Deficiency Control T lymphocyte function Control nitric oxide production (not shown) Profoundly suppress the immune system Increase the susceptibility to infection 66

67 Myeloid cell Arginine CATs Arginase Ornithine 67

68 Arginine Deficiency Syndrome A set of signs and symptoms associated with the loss of a specific nutrient T-lymphocyte dysfunction NO production Clinical consequences Increased infections, poor microcirculation, poor wound healing Mechanism - Arginase Therapy- Surgical Immunonutrition Protocol (Popovic, Zeh, Ochoa 2006) 68

69 Arginase 1 is Increased after Trauma Control 6h 12h 24h 48h 72h ARG 1 Control Makarenkova et. Al. J. Imm

70 Arginase 1 in Myeloid cells Metabolize Arginine - MDSC Makarenkova, Ochoa Journal of Immunoloy 2006 MDSC = Myeloid Derived Suppressor Cells 70

71 Human Leukocyte Arginase I Protein Expression after Surgery + Internal Control Preop Postop Preop Postop Preop Postop Pt 1 Pt 2 Pt 3 Tsuei et. al. J. Trauma

72 Arginine Plasma Levels Drop after physical injury (i.e. surgery) Rapid (minutes/hours) Requires replacement Arginine Plasma Levels and disease Process Conditionally Essential micromolar Arg Decrease proportionally to the severity of injury Control Trauma Sepsis Ochoa et al. Ann Surg

73 Arginine is essential for Normal T- cell proliferation CD8 CD4 Poly. (CD8) Poly. (CD4) Proliferation M 12.5 M 25 M 50 M 100 M 150 M 500 M 1000 M Arginine Concentration R 2 = R 2 = Ochoa Lab Archive 73

74 T-Lymphocyte Function after Surgery Decreased Anergy of recall antigens Development of memory Cytotoxicity IL-2 production Interferon gamma production T-cell receptors Increased susceptibility to infection Zhu et al Crit Care Clin. 2010:26;

75 Arginine deficiency causes T-cell Dysfunction Arginine Deficiency Syndrome T-Cell Dysfunction INFECTION Risk 75

76 Supplementing Arginine Therapies aimed at restoring T cell function have failed with one exception Supraphysiologic quantities ~15 g/liter (15-30 grams per day) Normal intake 3-5 grams per day Increases plasma arginine levels Aimed at restoring a nutrient deficiency Ochoa et al. Nutr Clin Prac. 2004;19:

77 Is Arginine the Whole Story? n-3 fatty acids EPA and DHA from Fish Oil Minimize inflammatory response by decreasing production of inflammatory mediators Increase immune response by enhancing lymphocyte function Interaction with Arginine? Remember: Marik et al found the combination of arginine and fish oil required for benefit in major elective surgical patients Calder P. Am J Clin Nutr Jun;83(6 Suppl):1505S-1519S. 77

78 Fish oil may Blunt Arginase 1 Expression PGE1 Borage Oil PGE2 Corn Oil PGE3 Fish Oil Arginase expression may be modified by the type of Fatty Acid Given to a Patient Bansal and Syres JPEN

79 The Role of Nucleotides Building blocks for DNA and RNA Indispensable in stressed states Essential for rapidly replicating cells to help support immune function Required for almost all cell activities and growth Arginine helps stimulate synthesis in vitro Yamauchi K et al. Nutrition (2002) 79

80 Surgical Immunonutrition Protocol - A New Standard of Care 5 Days Preoperatively At least 5 Days Postoperatively if feasible 500 ml 1000 ml IMF formula/day At least 1000 kcal IMF formula/day (meet at least 50-65% of needs) Waitzburg 2006; Marik 2010; McClave 2009; August 2009; Drover 2011 IMF= Immunonutrition Formula 80

81 Keys to Compliance Nutritional Assessment that involves the team and is discussed with the patient Surgeon stressing importance of nutrition- the basics first, the peri-operative protocol second Education with patient and caregiver on the basics and the surgical immunonutrition protocol Evans S. NNI Breakfast Seminar at ACS

82 Pre-operative Assessment General Assessment- Surgeon & Nurse involved History and Physical Review of Systems Diet and Nutrition Current Complaints with Diagnosis Discussion of surgery Evans S. NNI Breakfast Seminar at ACS

83 Nutritional Assessment Criteria 5% usual body weight loss in past month 10% usual body weight loss in past 6 months Low serum albumin (see lab normal) Mini Nutrition Assessment (MNA ) score 7 (age 65+) Body Mass Index (BMI) < 18.5 kg/m2 (age < 75) < 22 (age 75) Evans S. NNI Breakfast Seminar at ACS

84 Nutrition: What s on the plate (well in advance of surgery)? Calorie needs Protein needs Fruit/Veg Protein Portion size 6 small meals Starch Evans S. NNI Breakfast Seminar at ACS

85 Pre-Surgical Immunonutrition 3 servings (8 oz each) per day for 5-7 days prior to surgery Immunonutrition Drink contains supplementary: Arginine Nucleotides Omega-3 fatty acids Evans S. NNI Breakfast Seminar at ACS

86 Tools to Assist Pre-op Compliance Education of Clinical Staff Instructions for protocol Guidelines for Diabetes Immunonutrition available at clinic Samples (assist flavor choice) Daily reminder checklist for patient/caregiver Recipes A good relationship between the prescriber and a local home care company or pharmacy To provide ease of access and take care of billing Evans S. NNI Breakfast Seminar at ACS

87 Post-Surgical Immunonutrition Pt will receive Immunonutritional Supplementation (along with oral intake) that has arginine, omega -3 fatty acids and dietary nucleotides 2-3 times/day. Immunonutrition tube feeding used if needed Calorie count is taken in to consideration with wound healing. Patient is weighed daily to see if calorie intake is sufficient Evans S. NNI Breakfast Seminar at ACS

88 Conclusions- Part 2 Standard nutritional formulas and immunonutrition formulas are like apples and oranges A blend of immunonutrients may work synergistically to drive improved outcomes in major elective surgery patients The frame for a nutrition discussion and educational tools to implement a surgical immunonutrition protocol are both vital to compliance 88

89 Conclusions- In Review, Part I Surgical immunonutrition given peri-operatively supports Decreased infections Decreased complications Saving of healthcare costs Demonstrated in GI cancer surgery patients Surgical immunonutrition needs to be standard of care Call to action 89

90 Questions? Thank You Sponsor Disclosure: This presentation has been prepared and sponsored by Nestlé HealthCare Nutrition, Inc. The material herein is for educational purposes only. Reproduction or distribution of these materials is prohibited. Copyright 2011 Nestlé. All rights reserved. 90