Research Essentials Talk UF Jacksonville August 4, 2020 Strategy - PowerPoint PPT Presentation

Research Essentials Talk UF Jacksonville August 4, 2020

Strategy for Translational Team Science Testable Cartoons Imagination

The role of NIGMS P50 sponsored team science in our understanding of multiple organ failure Frederick A. Moore, MD, Ernest E. Moore, MD, Timothy R. Billiar, MD, Yoram Vodovotz, PhD, Anirban Banerjee, PhD, and Lyle L. Moldawer, PhD, Gainesville, Florida J Trauma Acute Care Surg 2017 Only discuss results related to the next cartoon Talk about Strategy

21 Institutes 6 Centers NIGMS 2019 budget $2.9 billion 95% basic, 5% clinical RCIPS Grants National Institute of General Medical Sciences (NIGMS)

Research Centers in Injury and Peri-operative Sciences “P50 RCIPS Grants” Team Science Around a Common Theme 3-5 Projects Led by Established Scientists Value-added Beyond Collection of RO1 Projects Primary Purpose Transform Knowledge P50

University of Colorado 1979-1996 Denver General ( DG ) General Surgery Resident Research was a core value Director of Surgical ICU

Denver General Hospital Surg Gyn Obstet 1977 Confusing & Important Topic Pick a Topic Became Our Research Focus Uncontrolled Sepsis Ben Eiseman

INJURY STRESS RESPONSE Autocannibolis ism

MOF Mortality 80%

Host Response to Blunt Trauma: Interrelationships of Anergy, Depressed Neutrophil Function, Nutritional Status and Sepsis NV Christou, MD, PhD; APH McLean MD and JL Meakins J Trauma 1980 JL Meakins Linked to Immunosuppression & Later Sepsis The influence of catabolism on immunocompetence in burned patients J.M. Hiebert MD, M. McGough, BA, G. Rodeheaver, PhD, J. Tobiasen,MA M.T. Edgerton, MD and R.F. Edlich MD, PhD Surgery 1979 RF Edlich Reversed by Nutritional Support (TPN) Effects of Protein Depletion and Repletion on Cell-mediated Immunity in Experimental Animals John M. Daly, MD, Stanley J. Dudrick, MD, Edward M. Copeland, MD. Ann Surg 1978 Stan Dudrick “Golden Age” of TPN

Nutrition Support Team Denver General Hospital Me Brother “Gene” PGY-3 Research Metabolic Fellow Cart

Cartoon # 1 Injury Stress Response Imagination Acute Protein Malnutrition  Muscle Mass  Visceral Protein  Organ Function  Immune Response Infection Multiple Organ Failure

Hypothesis Acute Protein Malnutrition  Muscle Mass  Visceral Protein Nutritional  Organ Function Support  Immune Response Infection Multiple Organ Failure

J Trauma 1986 J Trauma 1986 Early TEN vs. Delayed TPN J Trauma 1989 Decrease sed In Infection ons J Trauma 1989 J Trauma 1994 J Trauma 1994

J Trauma 1989 Early TEN vs. Early TPN Decrease sed In Infection ons Is TEN good or is TPN bad ?

J Trauma 1983 Eugene Faist MOF can occur without infection Visiting Professor

SYSTEMIC INFLAMMATORY RESPONSE Infection Tissue Injury Shock SIRS MOF Die Pancreatitis Limb Ischemia Recover “SEPSIS SYNDROME”

J Trauma 1988 Edwin A. Deitch Bacterial Translocation causes SIRS Visiting Professor

J Trauma 1989 Cartoon # 2 Gut: The Starter for MOF Figure 1 Liver: The Motor for MOF Liver Kupffer Kupffer Immune Immune Shock Shock PGE 2 = PGE 2 = Cell Cell Gut Gut IL-1 = IL-1 = Stress Stress Endotoxin Endotoxin Bacteria Bacteria TNF TNF C 3 a, C 5 a C 3 a, C 5 a - - ATN ATN O 2 O 2 Delayed Delayed Injured Tissue Injured Tissue Enteral Enteral ARDS ARDS Feeding Feeding

J Trauma 1989 Testable hypothesis: bacterial translocation via portal vein Gut: The Starter for MOF Figure 1 Liver: The Motor for MOF Liver Kupffer Kupffer Immune Immune Shock Shock PGE 2 = PGE 2 = Cell Cell Gut Gut IL-1 = IL-1 = Stress Stress Endotoxin Endotoxin Bacteria Bacteria TNF TNF C 3 a, C 5 a C 3 a, C 5 a - - ATN ATN O 2 O 2 Delayed Delayed Injured Tissue Injured Tissue Enteral Enteral ARDS ARDS Feeding Feeding

J Trauma 1989 Testable hypothesis: bacterial translocation via portal vein Gut: The Starter for MOF Figure 1 Liver: The Motor for MOF Liver Kupffer Kupffer Immune Immune Shock Shock PGE 2 = PGE 2 = Cell Cell Gut Gut IL-1 = IL-1 = Stress Stress Endotoxin Endotoxin Bacteria Bacteria TNF TNF C 3 a, C 5 a C 3 a, C 5 a - - ATN ATN O 2 O 2 Delayed Delayed Injured Tissue Injured Tissue Enteral Enteral ARDS ARDS Feeding Feeding

Alden Harken Alden Harken TRAUMA RESEARCH CENTER UNIVERSITY OF COLORADO UNIVERSO Intact New Chairman Animal Critically ill Patient Cells & Genes & Organs Molecules NIGMS P50 Team Science Grant

Alden Harken Alden Harken Study Your Patients! TRAUMA RESEARCH CENTER UNIVERSO DG SICU - CLINICAL CORE Intact Animal “Focus” Critically ill Patient Cells & Genes & Organs Molecules Organize ICU to be Research Lab

Clinical Specialist Position Standard Operating Procedures (SOPs) Sedation Analgesia ICP Management Pulmonary Care Ventilator Management and Weaning ARDS Rescue Protocol Shock Resuscitation Protocol Enteral Feeding Protocol Jim Heanel Stress Ulcer Prophylaxis DVT Prophylaxis Bedside Procedure Team Metabolic Cart Studies Antibiotic Protocol Electrolyte Replacement

J Trauma 1991 20 Torso Trauma Resuscitation Patients Portal Vein Catheters & Sampled Blood X 5 days Clinical Relevance Hypothesis: bacterial translocation via portal vein is driving mechanism in MOF

J Trauma 1991 20 Torso Trauma Resuscitation Patients Portal Vein Catheters & Sampled Blood X 5 days Hypothesis: bacterial translocation via portal vein is driving mechanism in MOF

J Trauma 1991 20 Torso Trauma Resuscitation Patients Portal Vein Catheters & Sampled Blood X 5 days Win-Win Hypothesis Found no endotoxin or bacteria in portal vein

Cartoon # 3 Back to the Drawing Board Imagination Second First Hit Hit MULTIPLE ORGAN Vulnerable FAILURE Systemic Shock Inflammatory + Response Tissue Injury Recovery Protected Can not Early Resuscitate Death

Cartoon for P-50 Trauma Center Grant TRAUMA PRIMES CELLS Second First Hit Hit MULTIPLE ORGAN Priming FAILURE Systemic Shock Inflammatory + Response Tissue Injury Recovery Preconditioning Can not Early Resuscitate Death

The “Two - Hit” Model of Neutrophil Activation TRAUMA PRIMES CELLS Second First Hit Hit Multiple Organ Priming Failure Systemic Shock Inflammatory + Response Tissue Injury Recovery Preconditioning Can not Early Resuscitate Death

POSTINJURY NEUTROPHIL PRIMING AND ACTIVATION STATES: THERAPEUTIC CHALLENGES Botha AJ, Moore FA, Moore EE, Fontes B, Banerjee A, and Peterson VM: Shock 1993 Wrote a Review Article Abrie Botha Pete Peterson UK General Surgeon Pediatric Hematologist

Lung Lung Arch Surg 1992 Arch Surg 1992 Arch Surg 1992 Renato Poggetti Created clinically relevant lab model Renato Poggetti Create clinically relevant lab models Gut Ischemia Reperfusion Induced Reversible Acute Lung Injury 1 st Research Fellow 1 st Research Fellow

J Trauma 1994 45 Min SMA Occlusion Pathophysiologic Sequence Activates Gut PLA 2 Sequesters PMN’s in Gut Primes Circulating PMN’s Sequesters PMN’s in Lung Reversible Lung Injury Max Lung Leak at 12 hours and back to control by 24 hours

J Trauma 1994 45 Min SMA Occlusion Pathophysiologic Sequence Activates Gut PLA 2 Sequesters PMN’s in Gut Primes Circulating PMN’s Sequesters PMN’s in Lung Reversible Lung Injury 2 nd hit of LPS IP at 6 hour caused MOF & Death 2 nd hit of LPS IP at 6 hours MOF and death Maximum at 6 hour

Postinjury neutrophil priming and activation: An early vulnerable window (24 hours) Abraham J. Botha, MD, Frederick A. Moore, MD, Ernest E. Moore, MD, Fernando J. Kim, MD, Anirban Banerjee, PhD, and Verlyn M. Peterson, MD, Surgery 1995 Denver, Colo. V max of Superoxide Production after fMLP Stimulation MMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMM Focused observational studies done DG SICU patients Sequential systemic platelet-activating factor and interleukin 8 primes neutrophils in patients with trauma at risk of multiple organ failure . Br J Surg 1996

Postinjury neutrophil priming and activation: An early vulnerable window Abraham J. Botha, MD, Frederick A. Moore, MD, Ernest E. Moore, MD, Fernando J. Kim, MD, Anirban Banerjee, PhD, and Verlyn M. Peterson, MD, Surgery 1995 Denver, Colo. Focused observational studies done DG SICU patients Abraham J. Botha, MD, Frederick A. Moore, MD, Ernest E. Moore, MD, Angela Sauaia, MD, Anirban Banerjee, PhD, and Verlyn M. Peterson, MD J Trauma 1995 After 72 hours circulating PMN’s are non -responsive Sequential systemic platelet-activating factor and interleukin 8 primes neutrophils in patients with trauma at risk of multiple organ failure . Br J Surg 1996

J Trauma 1998 J Trauma 1998 Arch Surg 1992 Angela Sauaia Denver MOF Database Denver MOF Score Defined Clinical Dataset to Study MOF Linked to Research Data

BIMODEL MOF Frederick A. Moore, MD, Angela Sauaia, MD, Ernest E. Moore, MD, James B. Heanel, RRT, Jon M. Burch, MD and Dennis C. Lezotte, PhD J T Traum uma 1996 Denver MOF Database Early MOF Late MOF