robert martindale does sirs and cars exist 2012 saspen 2012
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Does IR and AR exist in 2012 ?
RobertGMartindaleMD,PhDProfessorandChief
.
1
DivisionofGeneralSurgery
OregonHealth
and
Science
University
PortlandOregonUSA
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The origins of the SIRS CARS concepts
Denver General HospitalDenver General HospitalSurg Gyn Obstet 1977
A New Syndrome
To Survive Single Organ Failure
Ben Eiseman
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Denver General HospitalDenver General HospitalSurg Gyn Obstet 1977
Infections
felt to be the cause
Infectious etiologyconcept supported
b ke a ers in
1970s Polk, Fry etc.
focused on
infectious etiology
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1970s > 50% of cases of MOF from
intraabdominal infections
1970s > 50% of cases of MOF from
intraabdominal infections
By 1980s IAI showing better outcomes but MOF By 1980s IAI showing better outcomes but MOF
s occurr ng a e same ra e as n e s
Better initial management of trauma and post op patients
s occurr ng a e same ra e as n e s
Better initial management of trauma and post op patients
Earlier recognition of IAI with the use of CT
Interventional radiolo ic techni ues allowin draina e of
Earlier recognition of IAI with the use of CT
Interventional radiolo ic techni ues allowin draina e of
abscess without open surgery
Series of papers from EU reporting MOF withoutabscess without open surgery
Series of papers from EU reporting MOF without
infection source
Faist- 1983 MOF in polytrauma
infection source
Faist- 1983 MOF in polytrauma uy nc w o e o y n amma on n rauma
Waydhas 1992 Inflammatory mediators infection,
trauma MOF
uy nc w o e o y n amma on n rauma
Waydhas 1992 Inflammatory mediators infection,
trauma MOF
All showing a convincing story that MOF occurs withoutinfection
All showing a convincing story that MOF occurs withoutinfection
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Many types of injury produce
a similar inflammation
Hunter J (1794) A treatise on blood,
inflammation and gunshot wounds
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Question 1980s: if not infection what was
drivin MOF ?
Question 1980s: if not infection what was
drivin MOF ?
Shock (septic, hemorrhagic, cardiogenic etc) Shock (septic, hemorrhagic, cardiogenic etc)
Concept that low flow states and tissue ischemia / Concept that low flow states and tissue ischemia /
Giving rise to gut origin of sepsis (multiple authors)
Gut as Motor for Multi le Or an Failure
Giving rise to gut origin of sepsis (multiple authors)
Gut as Motor for Multi le Or an Failure
unrecognized flow-dependent oxygen consumption Supranormal oxygen delivery (Shoemaker)
unrecognized flow-dependent oxygen consumption Supranormal oxygen delivery (Shoemaker)
Supporting evidence at the time Supporting evidence at the timeAnimal models of bacterial translocation
Selective gut decontamination in humans (+/-)
Animal models of bacterial translocation
Selective gut decontamination in humans (+/-)
Primarily pneumonia was improved
Primarily pneumonia was improved
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ICU admission sepsis- trauma- shock
Cardiac output Proinflammatorycytokine release
ncreasecatecholamines
Splanchnic hypoperfusion
vasoconstriction
Barrier
disruption
Reduced
mucosal bloodflow
Altered GI
motility
Changes inbacterial flora and
virulence
7
Schmidt H, Martindale R. Curr Opin Nutr Metab Care. 2003;6:587-591. Mutlu GM, et al. Chest. 2001;119:1222-1241.
, ,
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Gut IntegrityGut Integrity
MaintainingMaintaining
Gut IntegrityGut Integrity
Increased PermeabilityIncreased Permeability
Bacterial OvergrowthBacterial Overgrowth
Early EN maintains gut integrity, prevents bacterial overgrowthEarly EN maintains gut integrity, prevents bacterial overgrowth ncrease gut permea ty n e to an sease sever tyncrease gut permea ty n e to an sease sever ty Bacterial translocation to MLNs, peritoneum, blood in sepsisBacterial translocation to MLNs, peritoneum, blood in sepsis 22 Sepsis dose Pseudomonas, Staph, E Coli : gut
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New concepts in metabolism / sepsisNew concepts in metabolism / sepsis
John Daly Protein depletion alters CMI inexperimental animals (Ann Surg 1978)
John Daly Protein depletion alters CMI inexperimental animals (Ann Surg 1978)
Frank Cerra Septic Autocannibalism and failure
of exo enous nutritional su ort Ann Sur 1980
Frank Cerra Septic Autocannibalism and failure
of exo enous nutritional su ort Ann Sur 1980
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Loss of Lean Body Mass
Ann Surg 2001
and Outcome ?
in Patients with Severe Sepsis or Major Blunt Trauma 1
in Patients with Severe Sepsis or Major Blunt Trauma 1
- - Continues 9-12 days, still 21 days
16% TBP lost first 21 days (67% from muscle)
Continues 9-12 days, still 21 days
16% TBP lost first 21 days (67% from muscle)
? Mechanism, not just pro-inflammatory cytokines ? Mechanism, not just pro-inflammatory cytokines
Loss of lean body mass clinical consequences 2
10% impaired Immune function20% impaired wound and rehabilitation
30% pneumonia and pressure ulcers
40% Death neumonia
1) Plank. WJS 24:630-638, 20002) Martindale R Physiologic Basis of Surgery 2008
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Cerra F et al Ann Surg 1980
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Self vs Non-self theory 1960s (Burnet, Medawar Noble Prize) gives rise to
concept of alarmins or danger signals to activate system (Matzinger 1990)
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Sepsis syndrome SIRSSepsis syndrome SIRS
(1990s)(1990s)
derived syndrome noted for a segment of ICUderived syndrome noted for a segment of ICU
Bone R, coined term SIRS in JAMA 1992
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Focus of the 90s Putting the fire out !
Multiple attempts at trying to reverse SIRS
Human model uniformly unsuccessful
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J Trauma 996Denver MOF Database
J Trauma 996
Late MOF
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DYSFUNCTIONAL INFLAMMATORY RESPONSE
Moderate SIRS
SIRS ar y
ModerateImmunosupression
Immunosupression
Moore E, Moore F et al 1990s
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Immunologic Dissonance: A Continuing Evolution in Our Understanding
of the Systemic Inflammatory Response Syndrome (SIRS) and the Multiple
Roger C. Bone, MD Ann Intern Med 1996
Adaptive Immune ResponseSevereSIRS Early MOF
Adaptive Immune Response
TraumaModerate SIRS
Moderate
CARS
-
RESPONSE SYNDROME
SevereCARSRisk Factors
Host factors
CARS
Shock
Tissue injury
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Immunologic Dissonance: A Continuing Evolution in Our Understanding
of the Systemic Inflammatory Response Syndrome (SIRS) and the Multiple
Roger C. Bone, MD Ann Intern Med 1996
Adaptive Immune ResponseSevereSIRS Early MOF
Adaptive Immune Response
TraumaModerate SIRS
Moderate
CARS
-
RESPONSE SYNDROME
SevereCARSRisk Factors
Host factors
FCARS
Shock
Tissue injuryFor every ON switch in biological systems
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POSTINJURY MOF OCCURS AS A RESULT OF A
Severe
SIRS Early MOF
TraumaModerate SIRS
Moderate CARS
Severe
CARS
CARS becomes moniker
for all the defects noted in
the adapative immune responseno e n rauma, seps s;
dec Ag presentation
macrophage paralysis
inc apoptosis of T-cells and dendritic cellsshift from Th1 to Th2 lymphocyte phenotype
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The next 10 yrs learning the signals for the
inflammatory response !
The next 10 yrs learning the signals for the
inflammatory response !
PAMPs (pathogen associated molecular patterns)
LPS, lipoteichoic acid, Flagellin, bacterial DNA etc
PAMPs (pathogen associated molecular patterns)
LPS, lipoteichoic acid, Flagellin, bacterial DNA etc
bind the TLR system
Inflammation signals
bind the TLR system
Inflammation signals DAMPs (danger associated molecular patterns)
IL-1, HMGB1, IL-33, mitochondrial DNA, extracellular ATP
Accumulation of unfolded or misfolded roteins in lumen
DAMPs (danger associated molecular patterns)
IL-1, HMGB1, IL-33, mitochondrial DNA, extracellular ATP
Accumulation of unfolded or misfolded roteins in lumen
of ER ER stress sensors IRE2, PERK, ATF6
of ER ER stress sensors IRE2, PERK, ATF6
Highly conserved mechanism
Recognition of damaged proteins and organelles
Highly conserved mechanism
Recognition of damaged proteins and organellesqua y con ro
Promotes survival of the cell
Regulated by nutrients
qua y con ro
Promotes survival of the cell
Regulated by nutrients
Signals hypoxia, acidosis, nutrients Signals hypoxia, acidosis, nutrients
Martinez-Borra J J Adv Exp Med 2012
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SIRS CARS concepts startingSIRS CARS concepts starting
to show cracks ?to show cracks ?
CLP and various sepsis models with inflammatory CLP and various sepsis models with inflammatory
Human models Human models
attenuate the inflammatory response
Onl one successful resultin in FDA a roval
attenuate the inflammatory response
Onl one successful resultin in FDA a roval
Xigris (activated protein C) which has been
voluntarily withdrawn from market by Lily for post
Xigris (activated protein C) which has been
voluntarily withdrawn from market by Lily for postapproval studies showing no benefit
Xiao 2011 showing gene expression in trauma pts
approval studies showing no benefit
Xiao 2011 showing gene expression in trauma pts
Glue GrantGlue Grant
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A 12-Year Prospective Study of Postinjury Multiple Organ Failure
Has An thin Chan ed?
David J. Ciesla, MD; Ernest E. Moore, MD; Jeffrey L. Johnson, MD; Jon M. Burch, MD;
Cla C. Cothren MD An ela Sauaia MD
Arch Surg 2005Denver MOF Database
Move forward 10 years and
2nd Peak in MOF Disappeared (Why ?)
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. OKeefe, MD; Mitchell J.
Cohen MD L le L. Moldawer PhD Ronald Tom kins MD ScD Ronald V. Maier MD
the Inflammation and the Host Response to Injury Collaborative Research Program
Glue Grant Database Crit Care Med 2012
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What was responsible for theWhat was responsible for the
Some early ICU management principles were flawed Some early ICU management principles were flawed
and were changing during those years
High Tidal Volume Mechanical Ventilation
and were changing during those years
High Tidal Volume Mechanical Ventilation
Supranormal oxygen delivery Supranormal oxygen delivery
Liberal Blood Transfusion Practices Liberal Blood Transfusion Practices
High Volume Crystalloid Resuscitation High Volume Crystalloid Resuscitation
Intermittent Dialysis Intermittent Dialysis
Early TPN Early TPN
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Why did the second peakWhy did the second peak
sappearsappear Attention to ut erfusion Attention to ut erfusion
Better understanding of ACS
Evolution of the lethal triad conce t
Better understanding of ACS
Evolution of the lethal triad conce t Acidosis - - hypothermia - - coagulopathy
Dama e control sur er
Acidosis - - hypothermia - - coagulopathy
Dama e control sur er
Better organ failure management data driven Renal
Better organ failure management data driven Renal
Pulmonary
He atic
Pulmonary
He atic Coagulation support
Guidelines in CC mana ement
Coagulation support
Guidelines in CC mana ement
ARDS, Surviving Sepsis, Nutrition
ARDS, Surviving Sepsis, Nutrition
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Starting to see consistent implementation
Starting to see consistent implementation
ARDS NET ARDS NET
,
Surviving sepsis
,
Surviving sepsis
ar y aggress ve an o cs, e-esca a e w en cu ures
return
ar y aggress ve an o cs, e-esca a e w en cu ures
return
visceral perfusion
Gl cemic controlvisceral perfusion
Gl cemic control
Van de Berghe 80 to 110 mg/ dl 150 to 180 mg/dl
S ecific or an su ort
Van de Berghe 80 to 110 mg/ dl 150 to 180 mg/dl
S ecific or an su ort Pulmonary, renal, cardiac, coagulation
Pulmonary, renal, cardiac, coagulation
Early enteral within 48 hours Early enteral within 48 hours
Wh Ti i f E l E t l F di M t l iWh Ti i f E l E t l F di M t l i
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When: Timing of Early Enteral Feeding Meta-analysisWhen: Timing of Early Enteral Feeding Meta-analysis
Study
Author/Journal Parameters Study Design OutcomeMarik. CCM. 2001. Feeding < or >36 hr 15 studies
753 atients
Infections
LOS*
Lewis. BMJ. 2001.
(surgery patients)
NPO vs
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With the loss of the second peak of
MOF a new set of patients was
With the loss of the second peak of
MOF a new set of patients was
starting to emergestarting to emerge
ro onge s ays
Management of organ failure
ro onge s ays
Management of organ failure Renal, pulmonary, cardiac etc
Decreased lean body mass
Renal, pulmonary, cardiac etc
Decreased lean body mass
Similar to cachexia of cancer Poor wound healing
Similar to cachexia of cancer Poor wound healing
Pressure ulcers Pressure ulcers
Commonly transferred to LTAC
if in ICU > 21 days and transferred to LTAC survival
Commonly transferred to LTAC
if in ICU > 21 days and transferred to LTAC survival
at one year ranges in 40 to 50% range (1)at one year ranges in 40 to 50% range (1)
LTAC= Long term acute care (1) JAMA 2012
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Glue Grant
tested this hypothesis
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A Genomic Storm 75% of Genes Up or Down Regulated
-
C. Down-regulated Adaptive Immunity
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Glue Grant testing theGlue Grant testing the
SIRS CARS hypothesisSIRS CARS hypothesis
an cou
not be confirmed !
an cou
not be confirmed ! No evidence of second
hit phenomona
No evidence of second
hit phenomona
expression of genes involved in
both innate and adaptive
expression of genes involved in
both innate and adaptive
comp ca e ou come
uncomplicated outcome
complicated outcome
complicated outcome
Simultaneous pro- & anti-
inflammation
Simultaneous pro- & anti-
inflammation Dysregulated adaptive immuneresponse
Early innate
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Fulminant death
Early innate
immunity Chronic Low Grade InflammationA. Clinical
Response
MOF
PICS
Insult
Pro-
Inflammation
-
SIRSPersistent Inflammation
InflammationProtein Catabolism/Cachexia
Indolent Death
B. Individual
Cell
Response
TRegsMDSCs
Persistent Inflammatory/immunosuppressionCatabolism Syndrome (PICS)
Macrophage ParalysisDendritic
Cells
T Effector Cell Number and Function
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A Paradoxical Role for Myeloid-DerivedA Paradoxical Role for Myeloid-Derived
Supressor Cells in Sepsis and TraumaSupressor Cells in Sepsis and Trauma
-
(MDSC)
-
(MDSC)
insults
insults
Poor antigen presentation but cause inflammation
Poor antigen presentation but cause inflammation
Express arginase 1 which depletes endogenousExpress arginase 1 which depletes endogenous
Suppresses T cell response which requires arginine Suppresses T cell response which requires arginine
Moldawer LL et al Mol Med 2011
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A Novel Regulatory Cell PopulationA Novel Regulatory Cell Population
cells -
cells -, . ,, . ,
Arise with chronic inflammation and immunologicstress
Arise with chronic inflammation and immunologicstress
Bronte, Nat Rev Immunol 2005 Bronte, Nat Rev Immunol 2005
Highly conserved response to various
inflammatory insults
Highly conserved response to various
inflammatory insults Bronte Nature Reviews Immunol 2005 Bronte Nature Reviews Immunol 2005
F h MDSC i
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GranulocytesFactorsthatpromoteMDSCexpansion
G/M/GMCSF
SCF
IL1IL
6
IL10
IL12
IL13
IL17
S100A8/9
ProstaglandinsHemopoeitic acrop ageVEGFSAA
CCL2
Stem Cells
X
DendriticCellCommon Myeloid Progenitor
Common Lymphoid ProgenitorReleased from Bone Marrow
& Populate Other Hemopoeitic Organs
Early innateCh i L G d I fl ti
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Fulminant death
y
immunity Chronic Low Grade InflammationA. Clinical
Response
MOF
PICS
Insult
Pro-
Inflammation
-
SIRSPersistent Inflammation
InflammationProtein Catabolism/Cachexia
Defects in Adaptive Immunity Indolent Death
B. Individual
Cell
Response
TRegsMDSCs
Macrophage ParalysisDendritic
Cells
T Effector Cell Number and Function
Early innateCh i L G d I fl ti
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Fulminant death
immunity Chronic Low Grade InflammationA. Clinical
Response
MOF
PICS
Insult
Pro-
Inflammation
-
SIRSPersistent Inflammation
InflammationProtein Catabolism/Cachexia
Defects in Adaptive Immunity Indolent Death
B. Individual
Cell
Response
TRegsMDSCs
Macrophage ParalysisDendritic
Cells
T Effector Cell Number and Function
Cli i l D t i t f PICSCli i l D t i t f PICS
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Clinical Determinants of PICSClinical Determinants of PICS
(surrogate markers)(surrogate markers)
Prolonged ICU/Hospital stay (>14 days)Prolonged ICU/Hospital stay (>14 days)
n amma on
C-Reactive Protein > 150 micrograms/dl
n amma on
C-Reactive Protein > 150 micrograms/dl
ImmunesupressionTotal lymphocyte count < 800 / mm
ImmunesupressionTotal lymphocyte count < 800 / mm
Catabolism
Wt loss >10% during hospitalization or BMI < 18
Catabolism
Wt loss >10% during hospitalization or BMI < 18Cr /Ht index < 80%
Albumin < 3.0 gm/dl
Cr /Ht index < 80%
Albumin < 3.0 gm/dl
Pre-albumin < 20 microgram /dlPre-albumin < 20 microgram /dl Gentile LF J Trauma 2012
Metabolic routes of ArginineMetabolic routes of Arginine1000
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Metabolic routes of ArginineMetabolic routes of Arginine
600
800
0
200
400
Control 6h 12h 24h 48h 72h
MDSC make largeamounts of ARGase
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Does SIRS and CARS happen in 2012:Does SIRS and CARS happen in 2012:
Conclusion 1Conclusion 1
explain the bimodal presentation of MOF
explain the bimodal presentation of MOF
Non-infection driven SIRS leading early MOFNon-infection driven SIRS leading early MOF
Late SIRS induced CARS causes infection drivenLate SIRS induced CARS causes infection driven
a ea e
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Conclusion 2 3Conclusion 2 3
2. With advances in ICU care the 2nd
peak in lateMOF disappeared in early 2000s
2. With advances in ICU care the 2nd
peak in lateMOF disappeared in early 2000s
3. However, the SIRS/CARS paradigm allowed us to 3. However, the SIRS/CARS paradigm allowed us todefine our current clinical challenges :
PICS or Persistent Inflammation and Immune
define our current clinical challenges :
PICS or Persistent Inflammation and Immune
Suppression Catabolism Syndrome1) Depressed adaptive immunity
Suppression Catabolism Syndrome1) Depressed adaptive immunity
2) Persistent low level of inflammation
3) Diffuse apoptosis
2) Persistent low level of inflammation
3) Diffuse apoptosis
5) Poor wound healing
6) Need to long term care and delay in return to function
5) Poor wound healing
6) Need to long term care and delay in return to function
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onc us ononc us on
inflammation & catabolism that characterizes PICS
inflammation & catabolism that characterizes PICS
Need to better understand these cells
How do we halt MDSC expansion ?
Need to better understand these cells
How do we halt MDSC expansion ?
Counteract their effects ?
Get them to mature into useful cell lines ?
Counteract their effects ?
Get them to mature into useful cell lines ?
Anabolic nutrition with specific nutrients may beAnabolic nutrition with specific nutrients may be
part of the answer !
arginine, fish oil, glutamine, anti-oxidants
part of the answer !
arginine, fish oil, glutamine, anti-oxidants
Strategy for Nutrition in the ICU 2012 :Strategy for Nutrition in the ICU 2012 :
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Goals Have Changed From Adjunctive SupportiveGoals Have Changed From Adjunctive Supportive
Previous goals = buying time until resolution (1970s to 2000s) Previous goals = buying time until resolution (1970s to 2000s)
Avoid metabolic complications
Current Goals: Aggressive focused intervention to prevent or
Avoid metabolic complications
Current Goals: Aggressive focused intervention to prevent or
therapy not support
therapy not support ,
Prevent oxidant stress Favorably modulate the inflammatory response
,
Prevent oxidant stress Favorably modulate the inflammatory response
Favorably modulate immune response
Enteral feeding (GALT)
Favorably modulate immune response
Enteral feeding (GALT)
ppropr a e macro an m cronu r en s
Glutamine, arginine, omega-3-FA, antioxidants
Stabilize mitochondria
ppropr a e macro an m cronu r en s
Glutamine, arginine, omega-3-FA, antioxidants
Stabilize mitochondria
Maintain healthy GI flora Maintain healthy GI flora
Decreaseinblind
lsepsis
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exploratory
laparotomysyndrome
performedin
patientswith
impendingMOF
ATLS
traumasystems
SIRS/CARS
ICU sepsis
ICU
technology
surgery
supranormalDO2
resuscitationadopted
PICS?
1970s 1990s 2000s 2010s1980s
Emergence
Emergenceof
MOF,
Epidemicof
Abdominal
o sepsis
syndromeACS&lateMOF
disappear
associated
withIAI
CompartmentSyndrome
(ACS)
MOF --- Sepsis syndrome --- SIRS --- SIRS/CARS--- SIRS/PICS -- ? Next
Summary: Does SIRS and CARS exist in 2012Summary: Does SIRS and CARS exist in 2012
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yy
ro a y no as was escr e n a e s
A new phase of cellular specific control is being
ro a y no as was escr e n a e s
A new phase of cellular specific control is being
MDSC, mitochondrial resuscitation
MDSC, mitochondrial resuscitation
our EB guidelines and protocols
Early aggressive sepsis management
our EB guidelines and protocols
Early aggressive sepsis management
Enteral is superior to parenteral feeding Metabolic and immune modulation Enteral is superior to parenteral feeding Metabolic and immune modulation
s o s, g utam ne, ant ox ants, arg n ne
Ventilator management
s o s, g utam ne, ant ox ants, arg n ne
Ventilator management
Glycemic control protocols Glycemic control protocols
So what terminology should weSo what terminology should we
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So what terminology should weSo what terminology should we
use o escr e our pa en suse o escr e our pa en s,
timing
,
timing
CARS should probably be deleted from ICU
CARS should probably be deleted from ICU
voca u aryvoca u ary
PICS or something similar (MARS) to describe the
chronic ICU populations
PICS or something similar (MARS) to describe the
chronic ICU populations
MARS = Mixed antagonists response syndrome
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