D SIRS d CARS i i 2012 ? Does SIRS and CARS exist in 2012 ?

RobertGMartindaleMD,PhD
ProfessorandChief
.
1
DivisionofGeneralSurgery
OregonHealthandScienceUniversity
PortlandOregonUSA
The origins of the SIRS CARS concepts
Denver General Hospital Denver General Hospital
Surg Gyn Obstet 1977
A New Syndrome
ICU Technology Allows Patients ICU Technology Allows Patients
To Survive Single Organ Failure
Ben Eiseman
Denver General Hospital Denver General Hospital Surg Gyn Obstet 1977
Infections
felt to be the cause
Infectious etiology
concept supported
by key papers in y y p p
1970s Polk, Fry etc.
Research in the 70s Research in the 70 s
focused on
infectious etiology
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
till i t th t i th 70 ?
By 1980s IAI showing better outcomes but MOF
till i t th t i th 70 ? still occurring at the same rate as in the 70s ?
Better initial management of trauma and post op patients
More potent and appropriately dosed antibiotics
still occurring at the same rate as in the 70s ?
Better initial management of trauma and post op patients
More potent and appropriately dosed antibiotics More potent and appropriately dosed antibiotics
Earlier recognition of IAI with the use of CT
Interventional radiologic techniques allowing drainage of
More potent and appropriately dosed antibiotics
Earlier recognition of IAI with the use of CT
Interventional radiologic techniques allowing drainage of g q g g
abscess without open surgery
Series of papers from EU reporting MOF without
g q g g
abscess without open surgery
Series of papers from EU reporting MOF without
infection source
Faist- 1983 MOF in polytrauma
N ti k 1987 h l b d i fl ti i t
infection source
Faist- 1983 MOF in polytrauma
N ti k 1987 h l b d i fl ti i t Nuytinck 1987 whole body inflammation in trauma
Waydhas 1992 Inflammatory mediators infection,
trauma, MOF
Nuytinck 1987 whole body inflammation in trauma
Waydhas 1992 Inflammatory mediators infection,
trauma, MOF ,
All showing a convincing story that MOF occurs without
infection
,
All showing a convincing story that MOF occurs without
infection
Many types of injury produce y yp j y p
a similar inflammation
Hunter J (1794) A treatise on blood,
inflammation and gunshot wounds
Question 1980s: if not infection what was
driving MOF ?
Question 1980s: if not infection what was
driving MOF ? gg
Shock (septic, hemorrhagic, cardiogenic etc)
seemed to be consistent with patients getting MOF
Shock (septic, hemorrhagic, cardiogenic etc)
seemed to be consistent with patients getting MOF seemed to be consistent with patients getting MOF
Concept that low flow states and tissue ischemia /
reperfusion is etiology becomes popular;
seemed to be consistent with patients getting MOF
Concept that low flow states and tissue ischemia /
reperfusion is etiology becomes popular; reperfusion is etiology becomes popular;
Giving rise to gut origin of sepsis (multiple authors)
Gut as Motor for Multiple Organ Failure
reperfusion is etiology becomes popular;
Giving rise to gut origin of sepsis (multiple authors)
Gut as Motor for Multiple Organ Failure p g
unrecognized flow-dependent oxygen consumption
Supranormal oxygen delivery (Shoemaker)
p g
unrecognized flow-dependent oxygen consumption
Supranormal oxygen delivery (Shoemaker)
Supporting evidence at the time Supporting evidence at the time
Animal models of bacterial translocation
Selective gut decontamination in humans (+/-)
Early enteral feeding showing benefit
Animal models of bacterial translocation
Selective gut decontamination in humans (+/-)
Early enteral feeding showing benefit Early enteral feeding showing benefit
Primarily pneumonia was improved
Early enteral feeding showing benefit
Primarily pneumonia was improved
Pathophysiology of Splanchnic Hypoperfusion Pathophysiology of Splanchnic Hypoperfusion Pathophysiology of Splanchnic Hypoperfusion Pathophysiology of Splanchnic Hypoperfusion
ICU admission sepsis- trauma- shock
Hypovolemia
I d
Hypovolemia
Cardiac output
Proinflammatory
cytokine release
Increased
catecholamines
Increased
Splanchnic hypoperfusion
Increased
vasoconstriction
Barrier
disruption
Reduced
mucosal blood
flow
Altered GI
motility
Changes in
bacterial flora and
virulence
Barrier Dysfunction MOF worsening sepsis
flow
7
Schmidt H, Martindale R. Curr Opin Nutr Metab Care. 2003;6:587-591. Mutlu GM, et al. Chest. 2001;119:1222-1241.
Barrier Dysfunction, MOF, worsening sepsis
Gut Integrity Gut Integrity

Maintaining Maintaining
Gut Integrity Gut Integrity
Increased Permeability Increased Permeability
Bacterial Overgrowth Bacterial Overgrowth
Early EN maintains gut integrity, prevents bacterial overgrowth Early EN maintains gut integrity, prevents bacterial overgrowth
I d bili li k d MOF d di i I d bili li k d MOF d di i
11
Increased gut permeability linked to MOF and disease severity Increased gut permeability linked to MOF and disease severity
11
Bacterial translocation to MLNs, peritoneum, blood in sepsis Bacterial translocation to MLNs, peritoneum, blood in sepsis
22
Sepsis dose Pseudomonas, Staph, E Coli : gut << IV Sepsis dose Pseudomonas, Staph, E Coli : gut << IV
33
11
Ammori ( J Gastrointest Surg 1999;3:252 ) Ammori ( J Gastrointest Surg 1999;3:252 )
22
Ljungqvist (J Trauma 2000;48:314) Ljungqvist (J Trauma 2000;48:314)
33
Alverdy (J Leuko Biol 2008:83:461) Alverdy (J Leuko Biol 2008:83:461)
New concepts in metabolism / sepsis New concepts in metabolism / sepsis
John Daly Protein depletion alters CMI in
experimental animals (Ann Surg 1978)
John Daly Protein depletion alters CMI in
experimental animals (Ann Surg 1978)
Frank Cerra Septic Autocannibalism and failure
of exogenous nutritional support (Ann Surg 1980)
Frank Cerra Septic Autocannibalism and failure
of exogenous nutritional support (Ann Surg 1980) of exogenous nutritional support (Ann Surg 1980) of exogenous nutritional support (Ann Surg 1980)
Loss of Lean Body Mass
Sequential Metabolic Changes Following Induction of SIRS Sequential Metabolic Changes Following Induction of SIRS
Ann Surg 2001
and Outcome ?
Sequential Metabolic Changes Following Induction of SIRS
in Patients with Severe Sepsis or Major Blunt Trauma
1
Sequential Metabolic Changes Following Induction of SIRS
in Patients with Severe Sepsis or Major Blunt Trauma
1
over REE peaks 4-5 days over REE peaks 4-5 days over REE peaks 4 5 days
Continues 9-12 days, still 21 days
16% TBP lost first 21 days (67% from muscle)
over REE peaks 4 5 days
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 function
20% impaired wound and rehabilitation
30% pneumonia and pressure ulcers
40% Death (pneumonia)
1) Plank. WJS 24:630-638, 2000
2) Martindale R Physiologic Basis of Surgery 2008
(p )
Cerra F et al Ann Surg 1980
Self vs Non-self theory 1960s (Burnet, Medawar Noble Prize) gives rise to
concept of alarmins or danger signals to activate system (Matzinger 1990)
Sepsis syndrome SIRS Sepsis syndrome SIRS
(1990s) (1990s)
SIRS becomes the popular term for inflammation SIRS becomes the popular term for inflammation SIRS becomes the popular term for inflammation
derived syndrome noted for a segment of ICU
patients
SIRS becomes the popular term for inflammation
derived syndrome noted for a segment of ICU
patients patients patients
Bone R, coined term SIRS in JAMA 1992
Focus of the 90s Putting the fire out !
Multiple attempts at trying to reverse SIRS
Some animal models successful Some animal models successful
Human model uniformly unsuccessful
BIMODEL MOF BIMODELMOF
J Trauma 1996
Denver MOF Database
J Trauma 1996
Early MOF Early MOF
Late MOF
POSTINJURY MOF OCCURS AS A RESULT OF A POSTINJURY MOF OCCURS AS A RESULT OF A
DYSFUNCTIONAL INFLAMMATORY RESPONSE
Severe
E l MOF
Trauma
Moderate SIRS
Severe
SIRS
Early MOF
Trauma
Severe
Moderate
Immunosupression
Severe
Immunosupression
Infections Late MOF Infections Late MOF
Moore E, Moore F et al 1990s
Immunologic Dissonance: A Continuing Evolution in Our Understanding
of the Systemic Inflammatory Response Syndrome (SIRS) and the Multiple
Organ Dysfunction Syndrome (MODS) Organ Dysfunction Syndrome (MODS)
Roger C. Bone, MD
Ann Intern Med 1996
Adaptive Immune Response
Lymphocytes
Severe
SIRS
Early MOF
Adaptive Immune Response
COMPENSATORY ANTI INFLAMMATORY
Lymphocytes
Trauma
Moderate SIRS
Moderate
CARS
COMPENSATORY ANTI-INFLAMMATORY
RESPONSE SYNDROME
Severe
CARS
Risk Factors
Host factors
CARS
Infections Late MOF
Shock
Tissue injury
Infections Late MOF
Immunologic Dissonance: A Continuing Evolution in Our Understanding
of the Systemic Inflammatory Response Syndrome (SIRS) and the Multiple
Organ Dysfunction Syndrome (MODS) Organ Dysfunction Syndrome (MODS)
Roger C. Bone, MD
Ann Intern Med 1996
Adaptive Immune Response
Lymphocytes
Severe
SIRS
Early MOF
Adaptive Immune Response
COMPENSATORY ANTI INFLAMMATORY
Lymphocytes
Trauma
Moderate SIRS
Moderate
CARS
COMPENSATORY ANTI-INFLAMMATORY
RESPONSE SYNDROME
Severe
CARS
Risk Factors
Host factors
F
CARS
Infections Late MOF
Shock
Tissue injury
For every ON switch in biological systems
we have an OFF switch
Infections Late MOF
we have an OFF switch
POSTINJURY MOF OCCURS AS A RESULT OF A
DYSFUNCTIONAL INFLAMMATORY RESPONSE DYSFUNCTIONAL INFLAMMATORY RESPONSE
Severe
SIRS
Early MOF
Trauma
Moderate SIRS
Moderate CARS
Severe
CARS
CARS becomes moniker
for all the defects noted in
the adapative immune response
t d i t i
Infections Late MOF
noted in trauma, sepsis;
dec Ag presentation
macrophage paralysis
dec T cell proliferation to stimulus
Infections Late MOF
dec T cell proliferation to stimulus
inc apoptosis of T-cells and dendritic cells
shift from Th1 to Th2 lymphocyte phenotype
The next 10 yrs learning the signals for the
inflammatory response !
The next 10 yrs learning the signals for the
inflammatory response !
Infectious signals Infectious signals Infectious signals
PAMPs (pathogen associated molecular patterns)
LPS, lipoteichoic acid, Flagellin, bacterial DNA etc
Infectious signals
PAMPs (pathogen associated molecular patterns)
LPS, lipoteichoic acid, Flagellin, bacterial DNA etc g
bind the TLR system
Inflammation signals
g
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 proteins in lumen
DAMPs (danger associated molecular patterns)
IL-1, HMGB1, IL-33, mitochondrial DNA, extracellular ATP
Accumulation of unfolded or misfolded proteins in lumen p
of ER
ER stress sensors IRE2, PERK, ATF6
Autophagy
p
of ER
ER stress sensors IRE2, PERK, ATF6
Autophagy Autophagy
Highly conserved mechanism
Recognition of damaged proteins and organelles
lit t l
Autophagy
Highly conserved mechanism
Recognition of damaged proteins and organelles
lit t l quality control
Promotes survival of the cell
Regulated by nutrients
quality control
Promotes survival of the cell
Regulated by nutrients g y
Signals hypoxia, acidosis, nutrients
g y
Signals hypoxia, acidosis, nutrients
Martinez-Borra J J Adv Exp Med 2012
SIRS CARS concepts starting SIRS CARS concepts starting
to show cracks ? to show cracks ?
Animal models Animal models Animal models
CLP and various sepsis models with inflammatory
blocking agents no benefit
Animal models
CLP and various sepsis models with inflammatory
blocking agents no benefit blocking agents no benefit
Human models
Over 150 RCT of various attempts to block or
blocking agents no benefit
Human models
Over 150 RCT of various attempts to block or Over 150 RCT of various attempts to block or
attenuate the inflammatory response
Only one successful resulting in FDA approval
Over 150 RCT of various attempts to block or
attenuate the inflammatory response
Only one successful resulting in FDA approval Only one successful resulting in FDA approval
Xigris (activated protein C) which has been
voluntarily withdrawn from market by Lily for post
Only one successful resulting in FDA approval
Xigris (activated protein C) which has been
voluntarily withdrawn from market by Lily for post
approval 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 Grant Glue Grant
A 12-Year Prospective Study of Postinjury Multiple Organ Failure
Has Anything Changed? y g g
David J . Ciesla, MD; Ernest E. Moore, MD; J effrey L. J ohnson, MD; J on M. Burch, MD;
Clay C. Cothren, MD; Angela Sauaia, MD y , ; g ,
Arch Surg 2005
Denver MOF Database
Move forward 10 years and
2nd Peak in MOF Disappeared (Why ?)
The Changing Pattern and Implications of Multiple Organ Failure 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. OKeefe, MD; Mitchell J.
Cohen, MD; Lyle L. Moldawer, PhD; Ronald Tompkins, MD, ScD; Ronald V. Maier, MD; , ; y , ; p , , ; , ;
the Inflammation and the Host Response to Injury Collaborative Research Program
Glue Grant Database
Crit Care Med 2012
What was responsible for the
loss of the second peak ?
What was responsible for the
loss of the second peak ? loss of the second peak ? loss of the second peak ?
Some early ICU management principles were flawed Some early ICU management principles were flawed y g p p
and were changing during those years
High Tidal Volume Mechanical Ventilation
y g p p
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
Why did the second peak
di ?
Why did the second peak
di ? disappear ? disappear ?
Attention to gut perfusion Attention to gut perfusion g p
Better understanding of ACS
Evolution of the lethal triad concept
g p
Better understanding of ACS
Evolution of the lethal triad concept o ut o o t e et a t ad co cept
Acidosis - - hypothermia - - coagulopathy
Damage control surgery
o ut o o t e et a t ad co cept
Acidosis - - hypothermia - - coagulopathy
Damage control surgery g g y
Better organ failure management data driven
Renal
g g y
Better organ failure management data driven
Renal Renal
Pulmonary
Hepatic
Renal
Pulmonary
Hepatic p
Coagulation support
Guidelines in CC management
p
Coagulation support
Guidelines in CC management Guidelines in CC management
ARDS, Surviving Sepsis, Nutrition
Guidelines in CC management
ARDS, Surviving Sepsis, Nutrition
Starting to see consistent implementation
of evidence based guidelines
Starting to see consistent implementation
of evidence based guidelines of evidence based guidelines of evidence based guidelines
ARDS NET
Lower TV VAP precautions
ARDS NET
Lower TV VAP precautions Lower TV, VAP precautions
Surviving sepsis
E l i tibi ti d l t h lt
Lower TV, VAP precautions
Surviving sepsis
E l i tibi ti d l t h lt Early aggressive antibiotics, de-escalate when cultures
return
Goal directed resuscitation to maintain organ and
Early aggressive antibiotics, de-escalate when cultures
return
Goal directed resuscitation to maintain organ and Goal directed resuscitation to maintain organ and
visceral perfusion
Glycemic control
Goal directed resuscitation to maintain organ and
visceral perfusion
Glycemic control y
Van de Berghe 80 to 110 mg/ dl 150 to 180 mg/dl
Specific organ support
y
Van de Berghe 80 to 110 mg/ dl 150 to 180 mg/dl
Specific organ support Spec c o ga suppo t
Pulmonary, renal, cardiac, coagulation
Nutrition for critical illness
Spec c o ga suppo t
Pulmonary, renal, cardiac, coagulation
Nutrition for critical illness Nutrition for critical illness
Early enteral within 48 hours
Nutrition for critical illness
Early enteral within 48 hours
When: Timing of Early Enteral Feeding Meta-analysis When: Timing of Early Enteral Feeding Meta-analysis
Study
Author/Journal Parameters Study Design Outcome
Marik. CCM. 2001. Feeding < or >36 hr 15 studies
753 patients
Infections
LOS* p
Lewis. BMJ. 2001.
(surgery patients)
NPO vs <24 hr 11 studies
837 patients
Infections
LOS
Vomiting risk Vomiting risk
Heyland. JPEN. 2003
(medical ICU)
<24 to 48 hr 8 studies Trend to infections
and mortality
Lewis SJ
J GI Surg 2008
< 24 hr 13 studies
1173 patients
Decrease mortality
DoigGS < 24 hr 5 studies Decrease infection
Int Care Med 2009
(Critically ill patients)
and mortality
Osland EJ <24 hr 15 studies 45%decrease in Osland EJ
J PEN 2011
(GI Surg with resection)
24 hr 15 studies
1240 patients
45% decrease in
morbidity
DoigGS <24 hr 3 studies Decrease mortality DoigGS
Injury 2010
(Trauma Pts)
< 24 hr 3 studies Decrease mortality
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 emerge starting to emerge
P l d ICU t P l d ICU t Prolonged ICU stays
Management of organ failure
Prolonged ICU stays
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
(1)
Commonly transferred to LTAC
if in ICU > 21 days and transferred to LTAC survival
(1)
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
Glue Grant
tested this hypothesis
A Genomic Storm 75% of Genes Up or Down Regulated
A. Gene expression After Severe Trauma B. Up-regulated Innate Immunity A. Gene expression After Severe Trauma B. Up regulated Innate Immunity
C. Down-regulated Adaptive Immunity
Glue Grant testing the Glue Grant testing the
SIRS CARS hypothesis SIRS CARS hypothesis
SIRS d CARS ld SIRS d CARS ld SIRS and CARS could
not be confirmed !
SIRS and CARS could
not be confirmed !
No evidence of second
hit phenomona
No evidence of second
hit phenomona
Exaggerated and prolonged Exaggerated and prolonged
li t d t
Exaggerated and prolonged
expression of genes involved in
both innate and adaptive
immunity discriminates
Exaggerated and prolonged
expression of genes involved in
both innate and adaptive
immunity discriminates
complicated outcome
uncomplicated outcome
immunity discriminates
complicated outcome
immunity discriminates
complicated outcome
Simultaneous pro- & anti-
inflammation
Simultaneous pro- & anti-
inflammation
Dysregulated adaptive immune
response
Early
Fulminant death
Early innate
immunity
Chronic Low Grade Inflammation
A. Clinical
Response
Early
MOF
Recovery
PICS
Insult
Pro-
Inflammation
Anti-
SIRS
CARS
Persistent Inflammation
Recovery
Anti
Inflammation
CARS
Protein Catabolism/Cachexia
Indolent Death
B. Individual
C ll
Macrophage Activation
Cell
Response
Macrophage Activation
TRegs
MDSCs
Persistent Inflammatory/immunosuppression
Catabolism Syndrome (PICS)
Macrophage Paralysis
Dendritic
Cells
T Effector Cell Number and Function
A Paradoxical Role for Myeloid-Derived A Paradoxical Role for Myeloid-Derived
Supressor Cells in Sepsis and Trauma Supressor Cells in Sepsis and Trauma
Induction of myeloid derived suppressor cells Induction of myeloid derived suppressor cells Induction of myeloid - derived suppressor cells
(MDSC)
Released from bone marrow after inflammatory
Induction of myeloid - derived suppressor cells
(MDSC)
Released from bone marrow after inflammatory Released from bone marrow after inflammatory
insults
Immature innate immune cells
Released from bone marrow after inflammatory
insults
Immature innate immune cells Immature innate immune cells
Poor antigen presentation but cause inflammation
Immature innate immune cells
Poor antigen presentation but cause inflammation
Express arginase 1 which depletes endogenous
arginine
Express arginase 1 which depletes endogenous
arginine arginine
Suppresses T cell response which requires arginine
arginine
Suppresses T cell response which requires arginine
Moldawer LL et al Mol Med 2011
A Novel Regulatory Cell Population
(MDSC)
A Novel Regulatory Cell Population
(MDSC) (MDSC) (MDSC)
Historically referred to as natural suppressor Historically referred to as natural suppressor Historically referred to as natural suppressor
cells
Bennette Proc Natl Acad Sci U S A 10:5142-4 1978
Historically referred to as natural suppressor
cells
Bennette Proc Natl Acad Sci U S A 10:5142-4 1978 Bennette, Proc Natl Acad Sci U S A.10:5142 4, 1978 Bennette, Proc Natl Acad Sci U S A.10:5142 4, 1978
Arise with chronic inflammation and immunologic
stress
Arise with chronic inflammation and immunologic
stress
Bronte, Nat Rev Immunol 2005 Bronte, Nat Rev Immunol 2005
Highly conserved response to various
inflammatory insults
Highly conserved response to various
inflammatory insults y
Bronte Nature Reviews Immunol 2005
y
Bronte Nature Reviews Immunol 2005
Granulocytes
FactorsthatpromoteMDSCexpansion
G/M/GMCSF
SCF
IL1
IL6
IL10
IL12
M h
IL13
IL17
S100A8/9
Prostaglandins
Hemopoeitic
Macrophage VEGF
SAA
CCL2
Stem Cells
X
DendriticCell
Common Myeloid Progenitor
Myeloid derived suppressor cells Myeloid derived suppressor cells
Common Lymphoid Progenitor
Released from Bone Marrow
& Populate Other Hemopoeitic Organs
Early
Fulminant death
Early innate
immunity
Chronic Low Grade Inflammation
A. Clinical
Response
Early
MOF
Recovery
PICS
Insult
Pro-
Inflammation
Anti-
SIRS
CARS
Persistent Inflammation
Recovery
Anti
Inflammation
CARS
Protein Catabolism/Cachexia
Defects in Adaptive Immunity
Indolent Death
B. Individual
C ll
Macrophage Activation
Cell
Response
Macrophage Activation
TRegs
MDSCs
Macrophage Paralysis
Dendritic
Cells
T Effector Cell Number and Function
Early
Fulminant death
Early innate
immunity
Chronic Low Grade Inflammation
A. Clinical
Response
Early
MOF
Recovery
PICS
Insult
Pro-
Inflammation
Anti-
SIRS
CARS
Persistent Inflammation
Recovery
Anti
Inflammation
CARS
Protein Catabolism/Cachexia
Defects in Adaptive Immunity
Indolent Death
B. Individual
C ll
Macrophage Activation
Cell
Response
Macrophage Activation
TRegs
MDSCs
Macrophage Paralysis
Dendritic
Cells
T Effector Cell Number and Function
Clinical Determinants of PICS Clinical Determinants of PICS
(surrogate markers) (surrogate markers)
Persistance: Persistance: Persistance:
Prolonged ICU/Hospital stay (>14 days)
I fl ti
Persistance:
Prolonged ICU/Hospital stay (>14 days)
I fl ti Inflammation
C-Reactive Protein > 150 micrograms/dl
Inflammation
C-Reactive Protein > 150 micrograms/dl
Immunesupression
Total lymphocyte count < 800 / mm
Immunesupression
Total lymphocyte count < 800 / mm
Catabolism
Wt loss >10% during hospitalization or BMI < 18
Catabolism
Wt loss >10% during hospitalization or BMI < 18
Cr /Ht index < 80%
Albumin < 3.0 gm/dl
Cr /Ht index < 80%
Albumin < 3.0 gm/dl
Pre-albumin < 20 microgram /dl Pre-albumin < 20 microgram /dl
Gentile LF J Trauma 2012
Metabolic routes of Arginine Metabolic routes of Arginine
600
800
1000
0
200
400
Control 6h 12h 24h 48h 72h
MDSC make large
amounts of ARGase
Does SIRS and CARS happen in 2012: Does SIRS and CARS happen in 2012:
Conclusion 1 Conclusion 1
SIRS/CARS paradigm arose in the mid 1990s to SIRS/CARS paradigm arose in the mid 1990s to SIRS/CARS paradigm arose in the mid 1990s to
explain the bimodal presentation of MOF
SIRS/CARS paradigm arose in the mid 1990s to
explain the bimodal presentation of MOF
Non-infection driven SIRS leading early MOF Non-infection driven SIRS leading early MOF
Late SIRS induced CARS causes infection driven
l t MOF
Late SIRS induced CARS causes infection driven
l t MOF late MOF late MOF
Conclusion 2 3 Conclusion 2 3
2. With advances in ICU care the 2
nd
peak in late
MOF disappeared in early 2000s
2. With advances in ICU care the 2
nd
peak in late
MOF disappeared in early 2000s
3. However, the SIRS/CARS paradigm allowed us to 3. However, the SIRS/CARS paradigm allowed us to
define our current clinical challenges :
PICS or Persistent Inflammation and Immune
define our current clinical challenges :
PICS or Persistent Inflammation and Immune
Suppression Catabolism Syndrome
1) Depressed adaptive immunity
Suppression Catabolism Syndrome
1) Depressed adaptive immunity
2) Persistent low level of inflammation
3) Diffuse apoptosis
4) Loss of lean body mass
2) Persistent low level of inflammation
3) Diffuse apoptosis
4) Loss of lean body mass 4) Loss of lean body mass
5) Poor wound healing
6) Need to long term care and delay in return to function
4) Loss of lean body mass
5) Poor wound healing
6) Need to long term care and delay in return to function ) g y ) g y
C l i 4 C l i 4 Conclusion 4 Conclusion 4
Myeloid derived suppressor cells drive persistent Myeloid derived suppressor cells drive persistent Myeloid derived suppressor cells drive persistent
inflammation & catabolism that characterizes PICS
N d b d d h ll
Myeloid derived suppressor cells drive persistent
inflammation & catabolism that characterizes PICS
N d b d d h ll 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 be Anabolic 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 :
Goals Have Changed From Adjunctive Supportive
Care to a Therapeutic Strategy
Strategy for Nutrition in the ICU 2012 :
Goals Have Changed From Adjunctive Supportive
Care to a Therapeutic Strategy Care to a Therapeutic Strategy Care to a Therapeutic Strategy
Previous goals = buying time until resolution (1970s to 2000s)
Attempt to preserve lean body mass
Previous goals = buying time until resolution (1970s to 2000s)
Attempt to preserve lean body mass Attempt to preserve lean body mass
Avoid metabolic complications
Current Goals: Aggressive focused intervention to prevent or
attenuate detrimental effects of ICU illness
Attempt to preserve lean body mass
Avoid metabolic complications
Current Goals: Aggressive focused intervention to prevent or
attenuate detrimental effects of ICU illness attenuate detrimental effects of ICU illness
therapy not support
Attenuate metabolic response prevent loss of LBM
attenuate detrimental effects of ICU illness
therapy not support
Attenuate metabolic response prevent loss of LBM Attenuate metabolic response, prevent loss of LBM
Prevent oxidant stress
Favorably modulate the inflammatory response
Appropriate lipid choices
Attenuate metabolic response, prevent loss of LBM
Prevent oxidant stress
Favorably modulate the inflammatory response
Appropriate lipid choices Appropriate lipid choices
Favorably modulate immune response
Enteral feeding (GALT)
A i t d i t i t
Appropriate lipid choices
Favorably modulate immune response
Enteral feeding (GALT)
A i t d i t i t Appropriate macro and micronutrients
Glutamine, arginine, omega-3-FA, antioxidants
Stabilize mitochondria
Appropriate macro and micronutrients
Glutamine, arginine, omega-3-FA, antioxidants
Stabilize mitochondria
Maintain healthy GI flora Maintain healthy GI flora
Decreaseinblind
exploratory
laparotomy
sepsis
syndrome
replaced with
Advances in
performedin
patientswith
impendingMOF
ATLS
traumasystems
damage control
replacedwith
SIRS/CARS
ICU sepsis
protocols Advancesin
ICU
technology
damagecontrol
surgery
supranormalDO
2
resuscitationadopted
PICS?
protocols
1970s 1990s 2000s 2010s 1980s
Emergence
f
Emergenceof
MOF,
Epidemicof
Abdominal
ofsepsis
syndrome
ACS&lateMOF
disappear
associated
withIAI
Compartment
Syndrome
(ACS)
MOF --- Sepsis syndrome --- SIRS --- SIRS/CARS--- SIRS/PICS -- ? Next
Summary: Does SIRS and CARS exist in 2012 Summary: Does SIRS and CARS exist in 2012
P b bl t it d ib d i l t 1990 P b bl t it d ib d i l t 1990 Probably not as it was described in late 1990s
A new phase of cellular specific control is being
addressed
Probably not as it was described in late 1990s
A new phase of cellular specific control is being
addressed addressed
MDSC, mitochondrial resuscitation
We must maintain what we have already learned via
addressed
MDSC, mitochondrial resuscitation
We must maintain what we have already learned via We must maintain what we have already learned via
our EB guidelines and protocols
Early aggressive sepsis management
We must maintain what we have already learned via
our EB guidelines and protocols
Early aggressive sepsis management y gg p g
Enteral is superior to parenteral feeding
Metabolic and immune modulation
Fi h il l i i id i i
y gg p g
Enteral is superior to parenteral feeding
Metabolic and immune modulation
Fi h il l i i id i i Fish oils, glutamine, antioxidants, arginine
Ventilator management
Specific organ support
Fish oils, glutamine, antioxidants, arginine
Ventilator management
Specific organ support Specific organ support
Glycemic control protocols
Specific organ support
Glycemic control protocols
So what terminology should we
t d ib ti t ?
So what terminology should we
t d ib ti t ? use to describe our patients ? use to describe our patients ?
SIRS yes but discuss source if possible and SIRS yes but discuss source if possible and SIRS yes, but discuss source if possible and
timing
SIRS yes, but discuss source if possible and
timing

CARS should probably be deleted from ICU

b l

CARS should probably be deleted from ICU

b l vocabulary vocabulary
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