egdt and septic shock

Emanuel P. Rivers, MD, MPH, IOM

Vice Chair and Research Director

Senior Staff in Emergency Medicine and Critical Care

Henry Ford Hospital

Clinical Professor, Wayne State University

Detroit, Michigan

Early Goal Directed Therapy inSevere Sepsis and Septic Shock:

Where are we 10 years later

Why Should You Botherwith Early Sepsis Intervention?

Time Sensitive DiseasesChanging the Paradigm of Practice

< 5%

Trauma

7%

Stroke

< 10%

AMI

Acute MyocardialInfarction Mortality - 10%

Liver TransplantMortality - 5%

Trauma Mortality - 5% Cardiac Surgery Mortality - 5%

Septic Shock Mortality– 50-55%

10% of Hospital Admissions – 40% of Hospital Deaths

$100 million in total hospital costs per year

HealthGrades analyzed over 5 million Medicarerecords of patients admitted through the emergencydepartment at 4,907 hospitals from 2006 through2008, to identify the top 5% of the best-performinghospitals in emergency medicine.

InflammationMicrocirculation

Early Goal DirectedHemodynamic Optimization

Organ Dysfunction

Decrease Mortality

Decrease Health Care ResourceConsumption

Early Detection of HighRisk Patients

AppropriateDisposition

ICU

ER

Collaboration is Fun

The Lecture Goals

The First Step:Understanding the Pathogenesis and

Expanding theLandscape of Sepsis

Global TissueHypoxia and

OrganDysfunction

Organism

Multiple OrganDysfunction and

Refractory Hypotension

Diffuse endothelialdisruption and

microcirculation defects

Systemic Inflammationor Inflammatory

Response

Septic Shock

Sepsis: A Complex and Dynamic Landscape

Severe Sepsis

EmergencyDepartment

Intensive CareUnit

Out PatientSetting

At Home orResidence

SepsisSource

Systemic Inflammatory Response Syndrome (SIRS)A clinical response arising from a nonspecific insult,including 2 of the following:

• Temperature ≥38oC or ≤36oC

• HR ≥90 beats/min

• Respirations ≥20/min

• WBC count ≥12,000/mm3 or≤4,000/mm3 or >10% bands

• PaCO2 < 32mmHg

General PracticeFloors

ORand Recovery

• 115 million visits/year.• 2.9% of hospital admits are

severe sepsis and septic shock.– 600,000 admissions per

year through the ED.• ED waiting times (5-6 hours)

approaching 24 hours.

• After ICU Admission:

– > 6 hour total delay forhemodynamic optimization.

– ICU is poor

• Shock mortality rate:

– ICU - 24% to 70%.

McCaig: MMWR, 2001, Angus DC et al. CCM, 2001,

Varon, CCM, 1997, Lundberg, 1998, CCM, Lefrant, 2000*, CCM

• 67 minute delay toICU arrival.#

• 3 fold increase inmortality.

General IPD Floors and Post OpICU

ED

Pre-Hospital

A Systems Approachand A Resuscitation

Golden Hours

Silver Day

Bundles

The Evidence behind theResuscitation Bundle

The Role of Antibiotics

• 2,154 septic shock patients

• Received antibiotics after theonset of recurrent or persistenthypotension

• Each hour of delay over 6 hrswas associated with 7.6%decrease in survival.

The Importance ofSource Control

• 54 y/o high school principlepresents with pyelonephritis,receives antibiotics.

• Radiography

• Remove infected devices

• Early Surgical Intervention

Crit Care Med, 2004

Sepsis is the friend of the elderly……. Greg Henry

Miss World FinalistMariana Bridi da Costa

Age 20, Dies From septic shock

“Doctors diagnosed her with aurinary track infection, her

condition worsened and doctorsthen diagnosed her with kidneystone and urinary tract infection

spread”

“She was hospitalized, requireddialysis and had her hands andfeet amputated in a bid to save

her from a deadly and little-knownillness”

The Diagnosisof Sepsis

is Imperfect

Stephen HalesStephen Hales -- 17331733

Outcome Implication of Not RecognizingA Subtle but Deadly Disease Transition

ER or Ward ICU

MAP ~ SVR X CO

The Physiology ofOxygen Transport:

Defining Tissue Hypoperfusion

250 ml/min

25%

1000 ml/min

SvO2 = 65-75%Hgb x SaO2

+ PaO2 x0.003 =

20 volume %

Cardiac Output5 liters/min.

Global Tissue Hypoxia:A More Sensitive Measure of Shock

OXYGENDEMAND

OXYGENDELIVERY

OXYGENBALANCE

Global TissueHypoxia

OXYGENDEMAND

OXYGENDELIVERY

Lactic Acid> 4 mM/L

70-75%

VO2

• Stress

• Pain

• Hyperthermia

• Shivering

• Work of breathing

DO2

• SaO2/PaO2

• Hgb

• Cardiac Output

- +

ScvO2 SvO2

Pope, Annals of Emerg Med, 2009

619 Patientsreceived EGDT

in 4 centers

Pope, Annals of Emerg Med, 2009

< 70% 70 - 90% > 90%

Risk Stratification or EarlyDetection of High Risk Patients:

The Use of Lactate

Diagnostic and Therapeutic Markers

SvO2

<2mM/L4 mM/L

38- 40%

Diagnostic and Therapeutic Markers

SvO2

4 mM/L

The Implications ofLactate Clearance

-30-20-10

01020304050607080

LactateClearance

%

1 2 3 4

Quartiles of Lactate Clearance

Lactate (ED or ICU Admission – (ED or ICU @ 6 hours)ED or ICU Length of Stay (hrs)

Early LactateClearance

0 12 24 36 48 60 726

3

4

5

6

7

8

9

10

11 No ClearanceIntermediate Clearance

High Clearance

Time (hr) p<0.05

MO

DS

53

42

29

16

0

10

20

30

40

50

60

Mo

rtali

ty(%

)

1 2 3 4

Debaker, 2006

7.73.8Lactate

5.311Central Venous Pressure

48.674ScvO2

51.244.8SAPS II

EGDTJAMA

48.4%34.8%Predicted Mortality

Systemic O2 Delivery (ml/min/m2)

SvO2Lactate

Critical O2 DeliveryThreshold

Sy

stem

icO

2C

onsu

mpti

on

(ml/

min

/m2)

EGDT JAMA

7.73.8Lactate

5.311CVP

48.674ScvO2

51.244.8SAPS

EGDTJAMA

Crit Care, 2009

50% of vasopressor-dependent septic shockpatients do not express lactic acidosis and

have higher mortalities

The Hemodynamic Perturbationsof Early Sepsis

Increased Metabolic Demands:Fever, Tachypnea Hypovolemia,Vasodilation &

Myocardial Depression

Microvascular Alterations:Impaired Tissue Oxygen

Utilization

Inflammatory Mediators Produce Cardiovascular Insufficiency

Cytopathic Tissue Hypoxia

Fink, Crit Care Clin, 2002

SepticShock

Goal Directed

DO2

- PaO2

- Hemoglobin

- Cardiac Output

Cardiac Optimization- Preload (CVP, PCWP, SVV)- Afterload (MAP, SVR)Contractility (SV)

- Heart Rate (BPM)- Coronary Perfusion Pressure

Microcirculation

CNS and Systemic VO2

- Stress

- Pain

- Hyperthermia

- Shivering

- Work of breathing

Endpoints of Resuscitation

Lactate

HappyCell

BaseDeficit

(a-v)CO2

SvO2

pHi

VO2

StO2

Excellence is performing commonthings in uncommon places….

George Washington Carver

Task Force of the American College ofCritical Care Medicine

Practice parameters for hemodynamicsupport of sepsis in adult patients in

sepsis.

Crit Care Med 1999 ;27:639-60

Fluids Vasopressors

Hematocrit of 30%

SvO2

LactateInotropes

Sepsis is a Spectrum of Disease

↑↑NormalVariableImpairment oftissue O2 utilization

↑↓↑VariableMyocardialSuppression

Variable↑Normal↓Compensated andvasodilatory

↑↓↓VariableHypovolemia

LactateScvO2

CVPFTcPPV

MAP

Vasodilators,r-APC

Correct anemiaInotropic Therapy

VasopressorsAdrenal Dysf.

Volume

Treatment andComments

• 62 year presents with sepsis after a prostate biopsy.• He also complains of SIRS, SOB and disorientation.• WBC of 25,000 and Lactate of 9 mM/L• Blood cultures and Antibiotics• 7 liters of fluid

May, 2006

7 liters of fluids in first6 hours and offvasopressors

Before Surgery

Day 2 – Extubated in theRecovery Room

10 liters of fluid in10 hours

Day 3 –Mobilization

93 years old Perforated Ulcer

Levophed – 10 ug/min

Although no difference in mortality at 60 days between the twotreatment groups, patients treated according to a conservativestrategy of fluid management (47 hours after ICU adm) had:

1. Significantly improved lung function and centralnervous system function

2. Decreased need for sedation, mechanicalventilation, and intensive care.

3. A small (0.3 day) increase in the number ofcardiovascular-failure–free days during the first 7 dayswith the liberal strategy.

These salutary effects were achieved without an increase in thefrequency of non-pulmonary organ failure or shock.

0 12 24 36 48 60 723 6

200

250

300

350Standard

EGDT

Hours after start of treatment

PaO

2/F

iO2

Ratio

PaO2/FIO2 Ratio

Sepsis is a Spectrum of Disease

↑↑NormalVariableImpairment oftissue O2 utilization

↑↓↑VariableMyocardialSuppression

Variable↑Normal↓Compensated andvasodilatory

↑↓↓VariableHypovolemia

LactateScvO2CVPMAP

Vasodilators,r-APC

Correct anemiaInotropic Therapy

VasopressorsAdrenal Dysf.

Volume

Treatment andComments

The Choice of a Vasopressor

Hypotensive

Tachycardic Patient

Hypotensive

Bradycardic Patient

Low Doseto High DoseVasopressor

No Vasopressorto High DoseVasopressor

0

20

40

60

NoVasopressor

No Vasopressorto Low DoseVasopressor

Mort

alit

y(%

)

20%

37%

58%54%

What do these individuals havein common?

Adrenal Insufficiency

Design: Randomized, double-blind,

multi-center

Patients: Septic shock

Intervention:

Hydrocortisone (50 mg every six hours)

Fludrocortisone (50 ug once per day)

Main Outcome: 28-day survival innonresponders to CST

Effect of Low Doses of Hydrocortisone andFludrocortisone on Mortality in

Patients with Septic Shock(Annane JAMA 2002)

229 Non-respondersRandomized

115 Treatment &

114 controls

10% decrease in

28-day mortality

17% reduction invasopressors use

Patients Receiving Vasopressors – Septic Shock

No OutcomeBenefit

Now what should I do about steroids?

The Original Trial

• 8 hour time frame

• Minimal steroid use

• 56% mortality

The Corticus Trial

• 72 hour time frame

• Excluded patientstreated – over 50%

• Less severe patients –30 - 40% mortality

• Similar benefit withhigher mortality

14.5% Reductionin Vasopressor

Use if Optimizedwith EGDT

Hold steroid useuntil the patient

has beenresuscitated and

endpoints met(6-8 hours)

Sepsis is a Spectrum of Disease

↑↑NormalVariableImpairment oftissue O2 utilization

↑↓↑ andBNP

VariableMyocardialSuppression

Variable↑Normal↓Compensated andvasodilatory

↑↓↓VariableHypovolemia

LactateScvO2

CVPFTcPPV

MAP

Vasodilators,r-APC

Correct anemiaInotropic Therapy

VasopressorsAdrenal Dysf.

Volume

Treatment andComments

Global TissueHypoxia

InflammatoryMediators

Parillo, JClin.Invest, 1985

Ms. Peterson

• Infected foot – clostridium Perf (anaerobe)

• Lactate of 10 and oliguric

• BNP -3467

• BUN-77 and creatinine 4.3

• CXR

• Ultrasound

Sepsis is a Spectrum of Disease

↑↑ ↑NormalVariableImpairment oftissue O2 utilization

↑↓↑VariableMyocardialSuppression

Variable↑Normal↓Compensated andvasodilatory

↑↓↓VariableHypovolemia

LactateScvO2

CVPFTcPPV

MAP

Vasodilators,r-APC

Correct anemiaInotropic Therapy

VasopressorsAdrenal Dysf.

Volume

Treatment andComments

Venous Hyperoxia in Sepsis

Pope, Annals of Emerg Med, 2009

< 70% 70 - 90% > 90%

Developing a sepsis quality improvement programis not as painful as it appears!

TimelyInterventionsUpon Arrival

24 hourBundle

Recognizingone has aproblem?

6 hourBundle

Early Stagingof IllnessSeverity

DefinitiveCare

ED or ICU?

ImprovedOutcomesAnd Costs

QualityAssurance

CMEandPeer

Uniformity

Understandingthe

Pathogenesis

Early Markers

Epidemiology

Current SepsisManagement

3 Conceptsof

Teams

DocumentationAnd Orders

The Devil is in the Details of a Sepsis Program

Documentation andStandard Operating Procedures

Early Sepsis Intervention SavesHospital Costs

54.336 Billion

183% Increaseover 8 years

20% Reduction in Sepsis Related CostsOr

$10 Billion of the $500 Billion inNational Health Care Savings

Roberta Mooney

Sepsis Coordinator at HFHS

DailyAssessment of

all admittedsepsis patients

Feed back to allclinicians

MonthlyMeetings andReports for allICU’s and ED

EGDT after a DecadeNEJM, 2001

Mo

rtali

ty%

Pre-EGDT Control EGDT

51%46%

30%

November 8, 2001

2009

2008

November, 2009

6125 Before

16-18%Mortality Reduction

0 10 20 30 40 50

Rivers, 2001Gao, 2005

Sebat, 2005Kortgen, 2006Shapiro, 2006

Trzeciak, 2006Micek, 2006

Shu-Min Lin, 2006Qu, 2006

Nguyen, 2007Chen, 2007

Jones, 2007Sebat, 2007

El Sohl, 2007Zubrow, 2008Zambon, 2008

Focth, 2009Moore, 2009

Puskarich, 2009Castellanos-Ortega, 2010

Cardoso, 2010Lefrant, 2010Crowe, 2010

Abstracts (4298 Patients)

Absolute Risk Reduction

5328 Before

0.0 2.5 5.0 7.5 10.0

Abstracts

Publications

Rivers, 2001

Number Need To Treat

1 of every 6Patients

Abstracts and Publications

5125 Before 4328 After

Which component of the sepsisbundle actually works?

The Future of SepsisManagement

What should I target formy next septic patient?

Lactate,Cultures, Antibiotics

Source ControlEGDT, r-APC

Vasopressin

Steroids

Norm GlycemicControl

Tight GlycemicControl