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Invited Review
The Evolving Rationale for Early Enteral Nutrition Based on Paradigms of Multiple Organ Failure
Frederick A. Moore, MD ; and Ernest E. Moore, MDNCP 2009
Frederick A. Moore MD
November 9 , 2012
Evolving Paradigms in Surgical Nutrition
Invited Review
The Evolving Rationale for Early Enteral Nutrition Based on Paradigms of Multiple Organ Failure
Frederick A. Moore, MD ; and Ernest E. Moore, MDNCP 2009
Stress Metabolism & Stress Formula TPN
SIRS/CARS Paradigm & Immune Enhancing Diets
Emergence of PICS & Anabolic Nutrition
Evolving Paradigms in Surgical Nutrition
Denver General HospitalSurg Gyn Obstet 1977
INFECTION
A New Syndrome
ICU Technology Allows Patients
To Survive Single Organ Failure
Ben EisemanBen Eiseman
Chief of Surgery
Ben Eiseman
Denver General HospitalSurg Gyn Obstet 1977
Pick a Topic
INFECTION
Ben Eiseman
MULTIPLE ORGAN FAILURE
UNCONTROLLED SEPSIS
Ben Eiseman
Septic AutocannibalismA 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 1980Septic AutocannibolismA 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
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
ACUTE PROTEIN MALNUTRITION
Muscle Mass
Visceral Protein
Organ Function
Immune Response
INFECTIONS
MULTIPLE ORGAN FAILURE
HYPOTHESIS
Aggressive Nutritional Support
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 1980sGREAT EXPECTATIONS
High branched chained amino acids
Perioperative TPN
Early enteral nutrition (EN) vs TPN
Early combined TPN and EN in ICU patientsnutrition
CLINICAL TRIALSTPN FAILED TO MEET EXPECTATIONS
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 evaluatedEarly supplemental PN increased risk of infection p <.05
Elke study5 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 19891. Herndon J Burn Care Rehab 1989, , 2. Bauer Int Care Med 20002. Bauer Int Care Med 2000
3.Heyland JPEN 20033.Heyland JPEN 2003, 4.Sena JACS 2008, 4.Sena JACS 2008, , 5.Elke CCM 20085.Elke CCM 2008
Early TPN in ICU patients is harmful
NEJM July 1 2011
4640 Patients with Nutrition Risk Score > 2 from 7 Belguim ICUs
2328Early EN (day 2)Late TPN (day 8)
2312Early EN (day 2)Early TPN (day 3)
USA Approach European Approach
Predefined Subgroup AnalysisEarly EN not Feasible due to Surgery
517 Patients ( APACHE II = 27 )
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)
*
*p=0.01
Nutrition 1990
Ann Surg 1992
J. WESLEY ALEXANDER
Frank B. Cerra
John M. Daly
JPEN 1990
IMMUNE ENHANCING DIETS - 1990s
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
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
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
Shock
Traumatic
Septic
Moderate SIRS
Severe SIRS
Infections Late MOF
Early MOF
SevereImmunosupression
Moderate Immunosupression
MOF OCCURS AS A RESULT OF A
DYSFUNCTIONAL INFLAMMATORY RESPONSE
Innate Immunity Neutrophils
Trauma Moderate SIRS
Severe SIRS
Infections Late MOF
Early MOF
SevereCARS
Moderate
CARS
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
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
Shock Moderate SIRS
Severe SIRS
Infections Late MOF
Early MOF
MOF OCCURS AS A RESULT OF A
DYSFUNCTIONAL INFLAMMATORY RESPONSE
SevereCARS
Moderate CARS
ImmunologicTrajectory of a Complicated ICU Course
Shock Moderate SIRS
Severe SIRS
Infections Late MOF
Early MOF
MOF OCCURS AS A RESULT OF A
DYSFUNCTIONAL INFLAMMATORY RESPONSE
SevereCARS
Moderate CARS
ImmunologicTrajectory of a Complicated ICU Course
Immune Enhancing Diets
2nd Peak in MOF Disappeared (Why ?)
A 12-Year Prospective Study of Postinjury Multiple Organ FailureHas 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 2005Denver MOF Database
Glue Grant Database Crit Care Med 2012
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 ACSepidemic
To address
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
More Consistent Implementation of Evidence Based CareDramatically 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 effectsof variable care on patient outcomes.
Glue Grant Experience
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
I'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
I'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
I'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
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 2006Simultaneous Pro- & Anti-inflammation
Block Pro-inflammation & Improve Mortality
But has no Effect on Anti-inflammation & CARS
J Immunology 2006
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 2006Simultaneous 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
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
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
Heat Map of ~ 2500 Genes
ctrl – control
12hrs,1,4,7,14, 21 & 28 daysfor individual patients
Blue – down regulated
Red- up regulated
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
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
Hypothesis
Deregulated Innate Immunity
Deregulated Adaptive Immunity
Complicated Outcome
SIRS - Excessive Innate Immune Response
CARS – Suppression Adaptive Immune Response
Uncomplicated Outcome
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
TRegsMDSCs
Dendritic Cells
T Effector Cell Number and Function
Insult
Persistent Inflammatory/immunosuppressionCatabolism Syndrome (PICS)
J Trauma 2112
Wrote a Review Article & Proposed a New Paradigm
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
TRegsMDSCs
Dendritic Cells
T Effector Cell Number and Function
Insult
Persistent Inflammation/immunosuppressionCatabolism Syndrome (PICS)
J Trauma 2112
10% Impaired immune function
20% Impaired wound healing & rehabilitation
30% Pneumonia & decubitus ulcers
40 % Indolent Death
% Lost
LOSS OF LEAN BODY MASSCLINICAL CONSEQUENCES
Potential PICS Patients – Persistent Inflammatory Hits
Burns ( > 30 % BSA )
Necrotizing pancreatitis
David Herndon
Burned Children Remain Catobolic > 1 yr
Anabolic Agents in Burned Children
Insulin
Propranolol
Oxandrolone
Exercise
Ann Surg 2008
UTMB - Galveston
Potential PICS Patients – Persistent Inflammatory Hits
Burns ( > 30 % BSA )
Major surgery complicated by severe sepsis
UF Shands 2000 – 2010 , 51,577 major surgery patients
2,404 (3.8%) develop severe sepsis
9%
82%
9%Azra Bihorac
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
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
Potential PICS Patients – Persistent Inflammatory Hits
Burns ( > 30 % BSA )
Major surgery complicated by severe sepsis
Prolonged mechanical ventilation
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)
Health Outcomes
90 (71%) Survive 3 months
Good
Fair
Poor
9
34
47
11 (9%) Good
3 Months 12 Months
30 (25%) Fair
27 (21%) Poor
Health Outcomes
90 (71%) Survive 3 months
Good
Fair
Poor
9
34
47
11 (9%) Good
3 Months 12 Months
30 (25%) Fair
27 (21%) Poor
19 (16%) Dead
45% 1 Year Mortality
Potential PICS Patients – Persistent Inflammatory Hits
Burns ( > 30 % BSA )
Major surgery complicated by severe sepsis
Prolonged mechanical ventilation
Sepsis
Long-term Cognitive Impairment and Functional Disability Among Survivors of Severe SepsisTheodore J. Iwashyna, MD, PhDE. Wesley Ely, MD, MPHDylan M. Smith, PhDKenneth 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
Long-term Cognitive Impairment and Functional Disability Among Survivors of Severe SepsisTheodore J. Iwashyna, MD, PhDE. Wesley Ely, MD, MPHDylan M. Smith, PhDKenneth 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
Cognitive Impairment of Survivors
Time to sepsis - 3.1 yrs. - 1.1 yrs. 0.9 yr 2.8 yrs
Before Sepsis After Sepsis
Cognitive impairment Mild
Moderate/severe
Second Survey Before Sepsis
Last Survey Before Sepsis
Second Survey After Sepsis
First Survey After Sepsis
6%
17% 17%
Pa
tie
nts
wit
h C
og
nit
ive
Imp
air
me
nt
%25%
20%
15%
10%
5%
0%
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 Fraction of Patients with Difficulty
0 0.2 0.4 0.6 0.8 1.0 0 0.2 0.4 0.6 0.8 1.0
Manage money
40%
Potential PICS Patients – Persistent Inflammatory Hits
Burns ( > 30 % BSA )
Major surgery complicated by severe sepsis
Prolonged mechanical ventilation
Sepsis
Trauma
Long-term Survival of Adult Trauma PatientsGiana H. Davidson, MD, MPHChristian A. Hamlat, MD, MPHFrederick P. Rivara, MD, MPHThomas D. Koepsell, MD, MPHGregory J. Jurkovich, MDSaman Arbabi, MD, MPH
JAMA, March 9, 2011
25% discharged to SNFs and > 1/3rd 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%
Fa
talit
y R
ate
Case Mortality Rate for Inpatients & 1 Year Postdischarge
Long-term Survival of Adult Trauma PatientsGiana H. Davidson, MD, MPHChristian A. Hamlat, MD, MPHFrederick P. Rivara, MD, MPHThomas D. Koepsell, MD, MPHGregory J. Jurkovich, MDSaman Arbabi, MD, MPH
JAMA, March 9, 2011
25% discharged to SNFs and > 1/3rd 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 mortalityF
ata
lity
Ra
te
Long-term Survival of Adult Trauma PatientsGiana H. Davidson, MD, MPHChristian A. Hamlat, MD, MPHFrederick P. Rivara, MD, MPHThomas D. Koepsell, MD, MPHGregory J. Jurkovich, MDSaman Arbabi, MD, MPH
JAMA, March 9, 2011
25% discharged to SNFs and > 1/3rd 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 > 1/3rd dead within one year.
Fa
talit
y R
ate Unchanged Combined
1 year mortality
Case Mortality Rate for Inpatients & 1 Year Postdischarge
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 2nd Peak in MOF Infection
MOF
Death
Glue Grant Database
Patients Ordered Top to Bottom by Time to Recovery (TTR)
No OrganDysfunction
Organ Dysfunction
Dead
Day 14
37%
MOF Recovery
Survival
Days after injury
0 7 days 14 days 21 days 28 days
Pro
po
rtio
n o
f p
atie
nts
Pat
ien
ts o
rder
ed b
y T
TR
B
A
A Paradoxical Role for Myeloid-Derived Suppressor CellsIn 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
A Paradoxical Role for Myeloid-Derived Suppressor CellsIn 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
A Paradoxical Role for Myeloid-Derived Suppressor CellsIn 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
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
Macrophage
Dendritic Cell
Granulocytes
Common Myeloid Progenitor
Myeloid derived suppressor cells
Factors that promote MDSC expansionG/M/GM-CSF
SCFIL-1IL-6
IL-10IL-12IL-13IL-17
S100A8/9Prostaglandins
VEGFSAACCL2
Common Lymphoid Progenitor
XX
Hemopoeitic Stem Cells
Released from Bone Marrow& Populate Other Hemopoeitic Organs
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
TRegsMDSCs
Dendritic Cells
T Effector Cell Number and Function
Insult
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
TRegsMDSCs
Dendritic Cells
T Effector Cell Number and Function
Insult
Conclusions
1) Early TPN to blunt stress matabolism sounds good , BUT!
Consistent signal from numerous studies over 30 years
Early TPN increases infectious complications
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
Conclusions
3. With advances in ICU care the 2nd 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
:
I'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)
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