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Invited Review

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

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Invited Review

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

  2. Invited Review The Evolving Rationale for Early Enteral Nutrition Based on Paradigms of Multiple Organ Failure Evolving Paradigms in Surgical Nutrition 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

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

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

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

  6. 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. Ann Surg 1980 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 Frank Cerra Buffalo General Hospital

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

  8. Beneficial Effects of Aggressive Protein Feeding In Severely Burned Children 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 Wes Alexander University of Cincinnati

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

  10. STRESS TPN FORMULATIONS OF 1980sGREAT EXPECTATIONS 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

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

  12. Early TPN in ICU patients is harmful 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 study5prospective 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

  13. NEJM July 1 2011 • 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 Approach European Approach

  14. Late TPN Early TPN

  15. Predefined Subgroup AnalysisEarly EN not Feasible due to Surgery 517 Patients ( APACHE II = 27 ) * p=0.01 Late TPN Early 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)

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

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

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

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

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

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

  22. Innate Immunity Neutrophils

  23. 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 Roger Bone Adaptive Immune Response Adaptive Immune Response Lymphocytes CARS Risk Factors Host factors Shock Tissue injury COMPENSATORY ANTI-INFLAMMATORY RESPONSE SYNDROME

  24. Adaptive Immunity Changes that Characterize CARS

  25. ImmunologicTrajectory of a Complicated ICU Course

  26. Immune Enhancing Diets ImmunologicTrajectory of a Complicated ICU Course

  27. 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 Arch Surg 2005 Denver MOF Database 2nd Peak in MOF Disappeared (Why ?) 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 Glue Grant Database

  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 To address the ACS epidemic

  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 Glue Grant Experience 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.

  31. Benchmarking Outcomes in Critically Injured Trauma Patients 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 Decreasing Mortality with Increasing Compliance to SOPs Driven By Quarterly Audits & Feedback 2005 2009 Study Year

  32. New Phenotype of Chronic Critical Illness has Replaced MOF 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 I'm

  33. New Phenotype of Chronic Critical Illness has Replaced MOF 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 I'm

  34. New Phenotype of Chronic Critical Illness has Replaced MOF 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 I'm

  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 J Immunology 2006 Simultaneous Pro- & Anti-inflammation Block Pro-inflammation & Improve Mortality But has no Effect on Anti-inflammation & CARS

  36. 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 J Immunology 2006 Simultaneous Pro- & Anti-inflammation Block Pro-inflammation & Improve Mortality But has no Effect on Anti-inflammation & CARS

  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 Trauma B. Up-regulated Innate 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 C. Down-regulated Adaptive Immunity

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

  40. Hypothesis Significant Findings The SIRS/CARS phenomenon cannot be confirmed. There is no evidence of a 2nd 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 SIRS - Excessive Innate Immune Response CARS – Suppression Adaptive Immune Response Deregulated Innate Immunity Complicated Outcome Uncomplicated Outcome Deregulated Adaptive Immunity

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

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

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

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

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

  46. Potential PICSPatients – 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 Azra Bihorac 9% 82% 9%

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

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

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

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