Robert Martindale Does SIRS and CARS Exist 2012 SASPEN 2012

5/25/2018 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


Response

MOF

PICS

Insult

Pro-

Inflammation

-



Defects in Adaptive Immunity Indolent Death

B. Individual

Cell

Response

TRegsMDSCs


Cells


Early innateCh i L G d I fl ti


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Fulminant death


Response

MOF

PICS

Insult

Pro-

Inflammation

-



Defects in Adaptive Immunity Indolent Death

B. Individual

Cell

Response

TRegsMDSCs


Cells


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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Robert Martindale Does SIRS and CARS Exist 2012 SASPEN 2012

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