1. Invited Review The Evolving Rationale for Early Enteral Nutrition Based on Paradigms of Multiple Organ Failure Frederick A. Moore, MD ; and Ernest E. Moore, MD NCP 2009 Frederick A. Moore MD November 9, 2012 Evolving Paradigms in Surgical Nutrition

2. Invited Review The Evolving Rationale for Early Enteral Nutrition Based on Paradigms of Multiple Organ Failure Frederick A. Moore, MD ; and Ernest E. Moore, MD NCP 2009 Stress Metabolism & Stress Formula TPN SIRS/CARS Paradigm & Immune Enhancing Diets Emergence of PICS & Anabolic Nutrition Evolving Paradigms in Surgical Nutrition

3. Denver General Hospital Surg Gyn Obstet 1977 INFECTION A New Syndrome ICU Technology Allows Patients To Survive Single Organ Failure Ben Eiseman Chief of Surgery Ben Eiseman

4. Denver General Hospital Surg Gyn Obstet 1977 Pick a Topic INFECTION Ben Eiseman MULTIPLE ORGAN FAILURE UNCONTROLLED SEPSIS Ben Eiseman

5. E John Daly University of Texas - Houston Ann Surg 1978

6. Septic Autocannibalism A Failure of Exogenous Nutritional Support FRANK B. CERRA, M.D., JOHN H.SIEGEL, M.D., BILL COLEMAN, JOHN R. BORDER,M.D.,RAPIER R. McMENAMY,PhD. Ann Surg 1980 Septic Autocannibolism A Failure of Exogenous Nutritional Support FRANK B. CERRA, M.D., JOHN H.SIEGEL, M.D., BILL COLEMAN, JOHN R. BORDER,M.D.,RAPIER R. McMENAMY,PhD. Frank Cerra Buffalo General Hospital Ann Surg 1980

7. INJURY STRESS RESPONSE Autocannibolism Epinephrine Glucagon Cortisol + Cytokines (TNF, IL1, IL6)

8. Wes Alexander University of Cincinnati J.WESLEY ALEXANDER MD, BRUCE G. MACMILLAN MD, J. DWIGHT STINNETT PhD, CORA K. OGLE PhD, RICHARD C. BOZIAN MD, JOSEF E. FISHER MD, JANE B. OAKES RD, ROMAINE KRUMMEL BSN Ann Surg 1980 Beneficial Effects of Aggressive Protein Feeding In Severely Burned Children

9. ACUTE PROTEIN MALNUTRITION  Muscle Mass  Visceral Protein  Organ Function  Immune Response INFECTIONS MULTIPLE ORGAN FAILURE HYPOTHESIS Aggressive Nutritional Support

10. High protein content Branched chain amino acids Lower Nonprotien Calorie / Gram of Nitrogen Ratio Decrease from traditional 150/1 to 100/1 Increased Percentage of Fat Do not stress glucose metabolism Designed based on better understanding of stress metabolism High protein content & special amino acids Lower nonprotein calorie / gram of nitrogen ratio to 100/1 Increased percentage of fat Goal : early positive caloric and nitrogen balance STRESS TPN FORMULATIONS OF 1980s GREAT EXPECTATIONS

11. High branched chained amino acids Perioperative TPN Early enteral nutrition (EN) vs TPN Early combined TPN and EN in ICU patientsnutrition CLINICAL TRIALS TPN FAILED TO MEET EXPECTATIONS

12. Early PN is Harmful in ICU patients Herndon Study 1 ( 39 Burn patients, TBSA >50% ) Immune suppression with PN (Tcell ratios) (days 7-14) Supplemental PN  mortality ( p<0.05 ) 63% v 26% EN alone Bauer study 2 (RCT 120 ICU patients) EN/PN v EN alone no Δ in ICU LOS or Mortality Heyland Meta-Analysis 3 : Trend toward greater mortality, increase $ No significant Δ in infection, hospital LOS, ventilator days Sena Study 4 : prospectively collected data, retrospectively evaluated Early supplemental PN increased risk of infection p <.05 Elke study 5 prospective study observational cross sectional, 1 day p prevalence 415 patients sepsis (454 ICU, 310 hospitals) PN associated with higher mortality, EN lowest mortality 1. Herndon J Burn Care Rehab 1989, 2. Bauer Int Care Med 2000 3.Heyland JPEN 2003, 4.Sena JACS 2008, 5.Elke CCM 2008 3.Heyland JPEN 2003, 4.Sena JACS 2008, 5.Elke CCM 2008 Early TPN in ICU patients is harmful

13. NEJM July 1 2011 4640 Patients with Nutrition Risk Score > 2 from 7 Belguim ICUs 2328 Early EN (day 2) Late TPN (day 8) 2312 Early EN (day 2) Early TPN (day 3) USA ApproachEuropean Approach

14. Late TPN Early TPN

15. Predefined Subgroup Analysis Early EN not Feasible due to Surgery 517 Patients ( APACHE II = 27 ) Late TPNEarly TPN % Infections 30% 40% Late TPN had 20% increase likihood of early discharge alive (hazard ratio = 1.2, 95 % CI 1.00 to 1.44, p=0.05) * * p=0.01

16. Nutrition 1990 Ann Surg 1992 J. WESLEY ALEXANDER Frank B. Cerra John M. Daly JPEN 1990 IMMUNE ENHANCING DIETS - 1990s

17. Nutrition 1990 Ann Surg 1992 JPEN 1990 IMMUNE ENHANCING DIETS - 1990s

18. Nutrition 1990 Ann Surg 1992 JPEN 1990 Different strategy Early enteral nutrition ( 24 - 48 hr of admission ) Modest dosing ( 14 - 18 kcal/kg/d ) Dosing limit ( 7 - 10 days ) IMMUNE ENHANCING DIETS - 1990s

19. Nutrition 1990 Ann Surg 1992 JPEN 1990 Different goals Maintain vital gut functions with enteral feeding Blood flow Motilty Barrier function Local immunity IMMUNE ENHANCING DIETS - 1990s

20. Nutrition 1990 Ann Surg 1992 JPEN 1990 Different goals Maintain vital gut functions Supplementation to modulate inflammation Arginine Glutamine Omega - 3 fatty acids Nucleotides IMMUNE ENHANCING DIETS - 1990s

21. BIMODEL MOF Denver MOF Database J Trauma 1996 Early MOF Late MOF

22. Innate Immunity Neutrophils

23. Risk Factors Host factors Shock Tissue injury Immunologic Dissonance: A Continuing Evolution in Our Understanding of the Systemic Inflammatory Response Syndrome (SIRS) and the Multiple Organ Dysfunction Syndrome (MODS) Roger C. Bone, MD Ann Intern Med 1996 Adaptive Immune Response Roger Bone CARS COMPENSATORY ANTI-INFLAMMATORY RESPONSE SYNDROME Adaptive Immune Response Lymphocytes

24. Increased Tregs Monneret, G, Debard, AL, Venet, F, et al., Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med, 2003. 31(7): p. 2068-71. T cell anergy Bone, RC. Sir Isaac Newton, sepsis, SIRS, and Cars. Crit Care Med, 1996 24(7): p.1125-8. Shift from THI to TH2 phenotype Delano, MJ, Scumpia, PO, Weinstein, JS, et al., MyD88- dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med, 2007. 204(6): p. 1463- 74. Macrophage Paralysis -decreased cytokine production -decreased bacterial clearance - decreased antigen presentation Munoz, C, Carlet, J, Fitting, C, et al., Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest, 1991. 88(5): p. 1747-54 Ayala, A and Chaudry, IH, Immune dysfunction in murine polymicrobial sepsis: mediators, macrophages, lymphocytes and apoptosis. Shock, 1996. 6 Suppl 1: p. S27-38 Lymphocyte Apoptosis Hotchkiss, R. S., Swanson, P. E., Cobb, J. P. et al. Apoptosis in lymphoid and parenchymal cells during sepsis: findings in normal and T- and B-cell-deficient mice. Crit Care Med, 1997 25(8): p. 1298-1307. Suppressed T cell proliferation De Waal Malefyt R, Haanen J, Spits H, et al: Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen- presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 1991; 174:915-924 Adaptive Immunity Changes that Characterize CARS

25. ImmunologicTrajectory of a Complicated ICU Course

26. Immune Enhancing Diets

27. 2nd Peak in MOF Disappeared (Why ?) A 12-Year Prospective Study of Postinjury Multiple Organ Failure Has Anything Changed? David J. Ciesla, MD; Ernest E. Moore, MD; Jeffrey L. Johnson, MD; Jon M. Burch, MD; Clay C. Cothren, MD; Angela Sauaia, MD The Changing Pattern and Implications of Multiple Organ Failure after Blunt Injury With Hemorrhagic Shock Joseph P.Minei, MD; Joseph Cuschieri, MD; Jason Sperry, MD; Ernest E. Moore, MD; Michael A. West, MD, PhD; Brian G. Harbrecht, MD; Grant E. O’Keefe, MD; Mitchell J. Cohen, MD; Lyle L. Moldawer, PhD; Ronald Tompkins, MD, ScD; Ronald V. Maier, MD; the Inflammation and the Host Response to Injury Collaborative Research Program Arch Surg 2005 Denver MOF Database Glue Grant Database Crit Care Med 2012

28. Fundamental Changes in Pre - ICU Care of Patients Arriving with Severe Bleeding Resuscitation – Permissive Hypotension Limit Crystalloids Massive Transfusion Protocols More Focus on Hemorrhage Control Whole Body CT Scanning Looking for Blushes Pelvic Fracture Protocols with Pelvic Packing the ACS epidemic To address

29. Recognition That Traditional ICU Care is Harmful High Tidal Volume Mechanical Ventilation Liberal Blood Transfusions Supranormal Oxygen Delivery Intermittent Dialysis Early TPN Late MOF/Deaths are Iatrogenic

30. More Consistent Implementation of Evidence Based Care Dramatically Reduces Mortality NIH funded study - $ 50 million 8 US Trauma Centers that had other NIH funding. Study the genomic response to trauma and its impact on patient outcomes. Need SOPs to control confounding effects of variable care on patient outcomes. Glue Grant Experience

31. 2009 2005 Joseph Cuschieri, MD; Jeffery L.Johnson, MD;Jason Sperry, MD; Michael A. West, M, PhD; Ernest E. Moore, MD; Joseph P.Minei, MD; et.al and the Inflammation and Host Response to Injury Large Scale Collaborative Research Program. Ann Surg 2012 Benchmarking Outcomes in Critically Injured Trauma Patients Decreasing Mortality with Increasing Compliance to SOPs Study Year Driven By Quarterly Audits & Feedback

32. I'mI'm Prolonged ICU stays Manageable Organ Dysfunctions Recurrent Infections (i.e. Hits) with Milder SIRS Persistent Acute Phase Response & # Lymphocytes Decreased Lean Body Mass – a Wasting Disease Poor Wound Healing & Decubitus Ulcers Transfer to LTACs for Indolent Deaths Poor Wound Healing & Decubitus Ulcers Transfer to LTACs for Indolent Deaths New Phenotype of Chronic Critical Illness has Replaced MOF & no Overt Late MOF

33. I'mI'm Prolonged ICU stays Manageable Organ Dysfunctions Recurrent Infections (i.e. Hits) with Milder SIRS Persistent Acute Phase Response & # Lymphocytes Decreased Lean Body Mass – a Wasting Disease Poor Wound Healing & Decubitus Ulcers Transfer to LTACs for Indolent Deaths Poor Wound Healing & Decubitus Ulcers Transfer to LTACs for Indolent Deaths & no Overt Late MOF New Phenotype of Chronic Critical Illness has Replaced MOF

34. I'mI'm Prolonged ICU stays Manageable Organ Dysfunctions Recurrent Infections (i.e. Hits) with Milder SIRS Persistent Acute Phase Response & # Lymphocytes Decreased Lean Body Mass – a Wasting Disease Poor Wound Healing & Decubitus Ulcers Transfer to LTACs for Indolent Deaths & no Overt Late MOF New Phenotype of Chronic Critical Illness has Replaced MOF

35. CARS is not Late & not Compensatory Basic Lab Observations Circulating Cytokine/Inhibitor Profiles Reshape the Understanding of the SIRS/CARS Continuum in Sepsis and Predict Mortality Marcin F. Osuchowski, Kathy Welch, Javed Siddiqui, Daniel G. Remick J Immunology 2006 Simultaneous Pro- & Anti-inflammation Block Pro-inflammation & Improve Mortality But has no Effect on Anti-inflammation & CARS J Immunology 2006

36. Circulating Cytokine/Inhibitor Profiles Reshape the Understanding of the SIRS/CARS Continuum in Sepsis and Predict Mortality Marcin F. Osuchowski, Kathy Welch, Javed Siddiqui, Daniel G. Remick J Immunology 2006 Simultaneous Pro- & Anti-inflammation Block Pro-inflammation & Improve Mortality But has no Effect on Anti-inflammation & CARS J Immunology 2006 CARS is not Late & not Compensatory Basic Lab Observations

37. Glue Grant Hypothesis (Tested in Humans) SIRS - Excessive Innate Immune Response CARS – Suppression Adaptive Immune Response Looking at the Genomic Response After Severe Blunt Trauma

38. A Genomic Storm – 75% of Genes Up or Down Regulated A. Gene expression After Severe TraumaB. Up-regulated Innate Immunity C. Down-regulated Adaptive Immunity Heat Map of ~ 2500 Genes ctrl – control 12hrs,1,4,7,14, 21 & 28 days for individual patients Blue – down regulated Red- up regulated

39. A Genomic Storm – 75% of Genes Up or Down Regulated A. Gene expression After Severe TraumaB. Up-regulated Innate Immunity C. Down-regulated Adaptive Immunity

40. Significant Findings The SIRS/CARS phenomenon cannot be confirmed. There is no evidence of a 2 nd hit Exaggerated and prolonged expression of genes involved in both innate and adaptive immunity discriminates complicated outcome Simultaneous pro- & anti- inflammation Failure to achieve homeostasis Hypothesis Deregulated Innate Immunity Deregulated Adaptive Immunity Complicated Outcome SIRS - Excessive Innate Immune Response CARS – Suppression Adaptive Immune Response Uncomplicated Outcome

41. Pro- Inflammation Anti- Inflammation SIRS CARS Early MOF Fulminant death Persistent Inflammation Recovery Protein Catabolism/Cachexia PICS Early innate immunity Chronic Low Grade Inflammation Indolent Death A. Clinical Response B. Individual Cell Response Macrophage Activation Macrophage Paralysis TRegs MDSCs Dendritic Cells T Effector Cell Number and Function Insult Persistent Inflammatory/immunosuppression Catabolism Syndrome (PICS) J Trauma 2112 Wrote a Review Article & Proposed a New Paradigm

42. Pro- Inflammation Anti- Inflammation SIRS CARS Early MOF Fulminant death Persistent Inflammation Recovery Protein Catabolism/Cachexia PICS Early innate immunity Chronic Low Grade Inflammation Indolent Death A. Clinical Response B. Individual Cell Response Macrophage Activation Macrophage Paralysis TRegs MDSCs Dendritic Cells T Effector Cell Number and Function Insult Persistent Inflammation/immunosuppression Catabolism Syndrome (PICS) J Trauma 2112

43.  10%Impaired immune function  20%Impaired wound healing & rehabilitation  30%Pneumonia & decubitus ulcers  40 % Indolent Death % Lost LOSS OF LEAN BODY MASS CLINICAL CONSEQUENCES

44. Potential PICS Patients – Persistent Inflammatory Hits Burns ( > 30 % BSA ) Necrotizing pancreatitis

45. David Herndon Burned Children Remain Catobolic > 1 yr Anabolic Agents in Burned Children Insulin Propranolol Oxandrolone Exercise Ann Surg 2008 UTMB - Galveston

46. Potential PICS Patients – Persistent Inflammatory Hits Burns ( > 30 % BSA ) Major surgery complicated by severe sepsis

47. UF Shands 2000 – 2010, 51,577 major surgery patients 2,404 (3.8%) develop severe sepsis 9% 82% 9% Azra Bihorac

48. 2,404 (3.8%) develop severe sepsis 9% 82% 9% Dead at 2 yrs. 14% 62% UF Shands 2000 – 2010, 51,577 major surgery patients

49. 2,404 (3.8%) develop severe sepsis 9% 82% 9% Dead at 2 yrs. 14% 62% Pathway to PICS UF Shands 2000 – 2010, 51,577 major surgery patients Rationale for sepsis screening

50. Potential PICS Patients – Persistent Inflammatory Hits Burns ( > 30 % BSA ) Major surgery complicated by severe sepsis Prolonged mechanical ventilation

51. Ann Intern Med 2010 1 year prospective cohort study from 5 adult ICUs at Duke 126 patients requiring prolonged ventilation 99 ( 79%) discharged alive 457 transitions in location of care (median 4) 150 hospital readmission ( ½ due to sepsis)

52. 457 Transitions in Care 150 Hospital readmissions ( ½ due to sepsis)

53. Health Outcomes 90 (71%) Survive 3 months Good Fair Poor 9 34 47 3 Months12 Months

54. Health Outcomes 90 (71%) Survive 3 months Good Fair Poor 9 34 47 11 (9%) Good 3 Months12 Months

55. Health Outcomes 90 (71%) Survive 3 months Good Fair Poor 9 34 47 11 (9%) Good 3 Months12 Months 30 (25%) Fair 27 (21%) Poor

56. Health Outcomes 90 (71%) Survive 3 months Good Fair Poor 9 34 47 11 (9%) Good 3 Months12 Months 30 (25%) Fair 27 (21%) Poor 19 (16%) Dead 45% 1 Year Mortality

57. Potential PICS Patients – Persistent Inflammatory Hits Burns ( > 30 % BSA ) Major surgery complicated by severe sepsis Prolonged mechanical ventilation Sepsis

58. Long-term Cognitive Impairment and Functional Disability Among Survivors of Severe Sepsis Theodore J. Iwashyna, MD, PhD E. Wesley Ely, MD, MPH Dylan M. Smith, PhD Kenneth M. Langa, MD, PhD JAMA, October 27, 2010 The Health and Retirement Study from 1996 to 2004 Americans > 50 years old were interviewed every 2 years Assessed cognitive and physical functional status Medicare claims - Identified who developed severe sepsis Compared two interviews before and after severe sepsis

59. Long-term Cognitive Impairment and Functional Disability Among Survivors of Severe Sepsis Theodore J. Iwashyna, MD, PhD E. Wesley Ely, MD, MPH Dylan M. Smith, PhD Kenneth M. Langa, MD, PhD JAMA, October 27, 2010 The Health and Retirement Study from 1996 to 2004 Americans > 50 years old were interviewed every 2 years Assessed cognitive and physical functional status Medicare claims - Identified who developed severe sepsis Compared two interviews before and two after severe sepsis

60. Cognitive Impairment of Survivors Time to sepsis - 3.1 yrs. - 1.1 yrs. 0.9 yr 2.8 yrs Before SepsisAfter Sepsis Cognitive impairment Mild Moderate/severe Second Survey Before Sepsis Last Survey Before Sepsis Second Survey After Sepsis First Survey After Sepsis 6% 17% Patients with Cognitive Impairment % 25% 20% 15% 10% 5% 0%

61. Changes in Activities of Daily Living (n=269)(n=169) Before Sepsis No Limitation Mild to Moderate Limitations Before sepsis After sepsis Walk Dress Bathe Eat Get into bed Toilet Prepare meal Grocery shop Use telephone Take meds Walk Dress Bathe Eat Get into bed Toilet Prepare meal Grocery shop Use telephone Take meds Manage money Fraction of Patients with Difficulty 0 0.2 0.4 0.6 0.8 1.0 Manage money 40%

62. Potential PICS Patients – Persistent Inflammatory Hits Burns ( > 30 % BSA ) Major surgery complicated by severe sepsis Prolonged mechanical ventilation Sepsis Trauma

63. Long-term Survival of Adult Trauma Patients Giana H. Davidson, MD, MPH Christian A. Hamlat, MD, MPH Frederick P. Rivara, MD, MPH Thomas D. Koepsell, MD, MPH Gregory J. Jurkovich, MD Saman Arbabi, MD, MPH JAMA, March 9, 2011 25% discharged to SNFs and > 1/3 rd died within one year. Washington State Trauma Database 124,421 patients over 13 years In hospital mortality 1995 1997 1999 2001 2003 2005 2007 16% 14% 12% 10% 8% 6% 4% Fatality Rate Case Mortality Rate for Inpatients & 1 Year Postdischarge

64. Long-term Survival of Adult Trauma Patients Giana H. Davidson, MD, MPH Christian A. Hamlat, MD, MPH Frederick P. Rivara, MD, MPH Thomas D. Koepsell, MD, MPH Gregory J. Jurkovich, MD Saman Arbabi, MD, MPH JAMA, March 9, 2011 25% discharged to SNFs and > 1/3 rd died within one year. Washington State Trauma Database 124,421 patients over 13 years In hospital mortality 1995 1997 1999 2001 2003 2005 2007 16% 14% 12% 10% 8% 6% 4% Case Mortality Rate for Inpatients & 1 Year Postdischarge Unchanged Combined 1 year mortality Postdischarge 1 year mortality Fatality Rate

65. Long-term Survival of Adult Trauma Patients Giana H. Davidson, MD, MPH Christian A. Hamlat, MD, MPH Frederick P. Rivara, MD, MPH Thomas D. Koepsell, MD, MPH Gregory J. Jurkovich, MD Saman Arbabi, MD, MPH JAMA, March 9, 2011 25% discharged to SNFs and > 1/3 rd died within one year. Washington State Trauma Database 124,421 patients over 13 years In hospital mortality 1995 1997 1999 2001 2003 2005 2007 16% 14% 12% 10% 8% 6% 4% Postdischarge 1 year mortality 25% discharged to SNFs and > 1/3 rd dead within one year. Fatality Rate Unchanged Combined 1 year mortality Case Mortality Rate for Inpatients & 1 Year Postdischarge

66. The Changing Pattern and Implications of Multiple Organ Failure after Blunt Injury With Hemorrhagic Shock Joseph P.Minei, MD; Joseph Cuschieri, MD; Jason Sperry, MD; Ernest E. Moore, MD; Michael A. West, MD, PhD; Brian G. Harbrecht, MD; Grant E. O’Keefe, MD; Mitchell J. Cohen, MD; Lyle L. Moldawer, PhD; Ronald Tompkins, MD, ScD; Ronald V. Maier, MD; the Inflammation and the Host Response to Injury Collaborative Research Program Crit Care Med 2012 1002 Severe Blunt Trauma 86 Died within 2 days 916 survive > 2 days 269 (29%) developed MOF No 2 nd Peak in MOF Infection MOF Death Glue Grant Database

67. Patients Ordered Top to Bottom by Time to Recovery (TTR) No Organ Dysfunction Organ Dysfunction Dead Day 14 37% MOF Recovery Survival Days after injury 0 7 days 14 days 21 days28 days Proportion of patients Patients ordered by TTR B A

68. Persistent Inflammation Immunosuppression Catabolism Inflammation Immunosuppression

69. Persistent Inflammation Immunosuppression Catabolism Inflammation Immunosuppression

70. A Paradoxical Role for Myeloid-Derived Suppressor Cells In Sepsis and Trauma Alex G Cuenca, Matthew J Delano, Kindra M. Scumpia, Claudia Moreno, Phillip O Scumpia, Drake M LaFace, Philip A Efron and Lyle L Moldawer Mol Med 2011 Crit Care Clin 2010 Linc Moldawer PhD University of Florida Dr NIH Inflammation

71. A Paradoxical Role for Myeloid-Derived Suppressor Cells In Sepsis and Trauma Alex G Cuenca, Matthew J Delano, Kindra M. Scumpia, Claudia Moreno, Phillip O Scumpia, Drake M LaFace, Philip A Efron and Lyle L Moldawer Mol Med 2011 Crit Care Clin 2010 Induction of myeloid - derived suppressor cells (MDSC) Released from bone marrow after inflammatory insults Immature innate immune cells Poor antigen presentation but cause inflammation Suppress T-cell responses through different mechanisms

72. A Paradoxical Role for Myeloid-Derived Suppressor Cells In Sepsis and Trauma Alex G Cuenca, Matthew J Delano, Kindra M. Scumpia, Claudia Moreno, Phillip O Scumpia, Drake M LaFace, Philip A Efron and Lyle L Moldawer Mol Med 2011 Crit Care Clin 2010 Induction of myeloid - derived suppressor cells (MDSC) Released from bone marrow after inflammatory insults Immature innate immune cells Poor antigen presentation but cause inflammation Suppress T-cell responses through different mechanisms

73. A Novel Regulatory Cell Population Myeloid Derived Suppressor Cells (MDSCs) Historically referred to as “natural suppressor cells” Bennette, Proc Natl Acad Sci U S A.10:5142-4, 1978 Arise with chronic inflammation and immunologic stress Bronte, Nat Rev Immunol 5:641-654, 2005 Highly conserved response to various inflammatory insults Bronte, Nat Rev Immunol 5:641-654, 2005

74. Macrophage Dendritic Cell Granulocytes Common Myeloid Progenitor Myeloid derived suppressor cells Factors that promote MDSC expansion G/M/GM-CSF SCF IL-1  IL-6 IL-10 IL-12 IL-13 IL-17 S100A8/9 Prostaglandins VEGF SAA CCL2 Common Lymphoid Progenitor X X Hemopoeitic Stem Cells Released from Bone Marrow & Populate Other Hemopoeitic Organs

75. Pro- Inflammation Anti- Inflammation SIRS CARS Early MOF Fulminant death Persistent Inflammation Recovery Protein Catabolism/Cachexia PICS Defects in Adaptive Immunity Early innate immunity Chronic Low Grade Inflammation Indolent Death A. Clinical Response B. Individual Cell Response Macrophage Activation Macrophage Paralysis TRegs MDSCs Dendritic Cells T Effector Cell Number and Function Insult

76. Pro- Inflammation Anti- Inflammation SIRS CARS Early MOF Fulminant death Persistent Inflammation Recovery Protein Catabolism/Cachexia PICS Defects in Adaptive Immunity Early innate immunity Chronic Low Grade Inflammation Indolent Death A. Clinical Response B. Individual Cell Response Macrophage Activation Macrophage Paralysis TRegs MDSCs Dendritic Cells T Effector Cell Number and Function Insult

77. Conclusions 1) Early TPN to blunt stress matabolism sounds good, BUT! Consistent signal from numerous studies over 30 years Early TPN increases infectious complications

78. Conclusions 2. SIRS/CARS paradigm arose in the mid 1990s to explain the bimodal presentation of MOF Immune enhancing diets were designed to blunt CARS

79. Conclusions 3. With advances in ICU care the 2 nd peak in late MOF disappeared in early 2000s 4. Ongoing research ? SIRS/CARS paradigm 5. However, the SIRS/CARS paradigm allowed us to define our current clinical challenge : PICS :

80. I'mI'm Prolonged ICU stays Manageable Organ Dysfunctions Recurrent Infections (i.e. Hits) with Milder SIRS Persistent Acute Phase Response & # Lymphocytes Decreased Lean Body Mass – a Wasting Disease Poor Wound Healing & Decubitus Ulcers Transfer to LTACs for Indolent Deaths & no Overt Late MOF Persistent Inflammation/immunosuppression Catabolism Syndrome (PICS)

81. Conclusions 6. Myeloid derived suppressor cells drive persistent inflammation & catabolism that characterizes PICS Need to better understand these cells How do we halt their expansion Counteract their effects Get them to mature Develop Strategies for Anabolic Nutrition