10/15/2016

1

Severe Sepsis and Septic Shock:Diagnosis and Management

Review and Update 2016

Emanuel Rivers , MD MPH

The Sunshine Act of Medical Transparency

No Disclosures

Saving patients from sepsis is a race against timeCDC calls sepsis a medical emergency;

encourages prompt action for prevention, earlyrecognition

Tuesday, August 23, 2016, 1:00 p.m. ET

10/15/2016

2

(Crit Care Med 2016; 44:1353–1360)

The Financial Impact

10/15/2016

3

33.164 Billionor

8.7% of aggregatehospital costs

What is Sepsis?:The Early Pathogenesis

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

10/15/2016

4

The Morbidity Impact

Morbidity orDisabilities

PsychiatricDisease

Chronic HeartFailure

Disabilities(Amputations)

Chronic LungDisease (ARDS)

Kidney Failureand Dialysis

NeuromuscularDisorders

The Realities of CurrentSepsis Management:

Need for Improving ASystem of Care and Disease

10/15/2016

5

Sepsis Care - 2016A Systems Approach To Poor Sepsis Care

Early Recognition (SIRS)+

Risk Stratification(Lactate)

Recognition ofpoor sepsis carein the US ED’s

HemodynamicOptimization

AndImmuomodulation

Cultures,Antibiotics andSource Control

Recognition ofGlobal TissueHypoxia and

Cryptic Shock

ContinuousQuality

Improvement

1955 2001

A Need to Change theParadigm of

Current Sepsis Management

10/15/2016

6

Cases/year Mortality (%)

Stroke 591,996 6-7

AMI 540,891 10

Trauma 697,025 5-16

Sepsis 859,858 15-20

Severe Sepsis 791,000 27-40

Septic Shock 200,000 36-47

Pneumonia 1,187,180 5-9

What AboutGuidelines for Sepsis?

10/15/2016

7

2004, 2008, 2012

• Maintains international data base representing over 40,000

patients to date.

• Consultant to CMS and NQF

• Continued refinement of sepsis best practice.

80-110to 150

Golden Hours

Silver Day

Bundles

NEJM, 2014

NEJM, 2014

NEJM, 2015

10/15/2016

8

Early GoalDirectedTherapy

UsualCare

Treatment EffectSIRS

LactateFluid Challenge

AntibioticsEarly ICU admission

Unblinded CareSteroids

Protective lung strategiesGlucose Control

Pre-existing Sepsis ProtocolsDiminishing Mortality

2001

2016

Mortality > 46.5%

Mortality <20%

NEJM, 2014

NEJM, 2014

NEJM, 2015

2001-

October 1, 2015

Joint Commission CMSAHRQ

10/15/2016

9

1. Measure lactate

2. Blood cultures/appropriate cultures

3. Give broad spectrum antibiotics

4. Fluid Challenge of 30 cc/ kg if (hypotension/lactate > 4mM/L)

3H

ou

rB

un

dle

6H

our

Bu

nd

le

5. If persistent hypotension– vasopressor to maintain MAP > 65 mmHg

6. Document perfusion:

7. Re-measure lactate within 6 hours

InvasiveCVP

ScvO2

UltrasoundIVCTEETTE

Dynamic Assessment ofVolume Responsivenessto Fluid Challenge or PLR

SVVSLR

Bioimpedence

Physical ExamPeripheral Pulses

Capillary Refill (<2 secs)Skin Turgor

Mottling ScoreShock Index

Diagnosing Severe Sepsis andSeptic Shock

The Origin of SIRS

1991

10/15/2016

10

SIRS in the Emergency Department

Tuttle A, Nowak Rm, Grzybowski M, Rivers EP, Dereczyk BE, Morris DC, Jaggi FM, Ander DS, Tomlanovich MC:The systemic inflammatory response syndrome at triage: prevalence and association with hospital admissions.

Acad Emergency Medicine 1996, 3(478).

Pneumonia and Creatinine of 4.2 mg/dl

isSevere Sepsis

10/15/2016

11

10/15/2016

12

The prognostic ability of qSOFAwas similar to that of SOFA andAPACHE II but slightly inferior to

that of MEDS.

The performance of qSOFA inpredicting ICU admission was

similar to that of SOFA,MEDS, and APACHE II.

Super SIRSSuspected Infection

Two or more:

• Temperature ≥38.3oC or ≤36oC

• HR ≥120 beats/min

• Respirations ≥24/min

• Systolic < 90 mmHg

10/15/2016

13

What are the physicalexamination findings of sepsis?

10/15/2016

14

10/15/2016

15

Antibiotic Therapy

Crit Care Med,2014

Crit Care Med,2014

8.5% Increase in Mortality

10/15/2016

16

Importance of Blood Cultures andAdequacy of Antibiotics

5,715 patients,Retrospective,

Multicenter

52%10.3% 9.45

10/15/2016

17

10/15/2016

18

The Importance ofSource Control

10/15/2016

19

Crit Care Med, 2004

Sigmoid Perforation in Association with Colonoscopy

Lu A, Aronowitz P. N Engl J Med 2012;366:744-744.

Every hour of delay from admission to surgery was associated with an adjusted2.4% decreased probability of survival compared with the previous hour.

10/15/2016

20

Risk Stratification for EarlyDetection of High Risk

Patients:

Changing the way we detectillness severity

Stephen Hales - 1733

SystolicBlood Pressure

DiastolicBlood Pressure

10/15/2016

21

A Subtle and Deadly Disease TransitionUsing a 279 year old definition

ER or Ward ICU

MAP ~ SVR X CO

250 ml/min

25%

1000 ml/min

SvO2 = 65-75% Hgb x 1.34 x SaO2

+ PaO2 x 0.003 =

20 volume %

Cardiac Output5 liters/min.

10/15/2016

22

70-75%

VO2

• Stress

• Pain

• Hyperthermia

• Shivering

• Work of breathing

DO2

• SaO2/PaO2

• Hgb

• Cardiac Output

- +

ScvO2 SvO2

Global Tissue Hypoxia:A More Sensitive Measure of Shock

OXYGENBALANCE

Global TissueHypoxia

OXYGENDEMAND

OXYGENDELIVERY

Lactic Acid> 4 mM/L

Where did a Lactate cut point of 4 come from?

56 patients with clinical signs of shock:Hypovolemia (17), Sepsis (9), cardiac failure (7),neural dys. & endocrine def. (4), vascular obs. (2),mixed (9), unclassified (8)

Broder G, Weil MH.Science 1964;143:1457-1459

Seminal Lactate Studies

10/15/2016

23

Screening for Severe IllnessInfection and Lactate (LA > 4 mM/L)

#SIRS SIRSWard (%)

SIRS + LAWard (%)

SIRS + LAICU

0 11.6 33.3 0

1 14.7 15.4 0

2 34.6 40.0 62.5

3 55.4 84.6 94.5

4 70.0 100 100

≥ 2 of the following is SIRS:

– 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

Grzybowski M, Tuttle A, Nowak R, Rivers EP, Dereczyk BE, Tomlanovich MC: : Systemic inflammatory response syndromecriteria and lactic acidosis in the detection of critical illness among patients presenting to the emergency department.

Chest 1996, 110:145S.

Lactate > 4 mM/L

28%

Low ScvO223%

Hypotension

28%

46% 51%

56%

35%

Crit Care Med, 2014

10/15/2016

24

Cardiovascular Insufficiency and Global Tissue Hypoxia:The Most Common Cause of Death in the First 24 hours

TachycardiaHypotension

Global TissueHypoxia

Brun-Buisson, C., F. Doyon, et al. (1995)."Incidence, risk factors, and outcome of severe sepsisand septic shock in adults.A multicenter prospectivestudy in intensive care units. French ICU Group for

Severe Sepsis." JAMA 274(12): 968-74.

Cryptic ShockSudden

CardiopulmonaryComplications

ED

Floors

20%

Check Initial and Repeat Lactate?

Case

• 78 year old female

• 2 weeks after AAA

• T – 39o C

• Cough

• Brown sputum

• Right sided chestpain

SvO24 mM/L

10/15/2016

25

12.1% of AllCardiac ArrestsAre pnuemonia

Repeat Lactate:The Implications ofLactate Clearance

10/15/2016

26

Quartiles of Lactate Clearance

Initial Lactate minus Later LactateInitial Lactate

Bad Good

Lactate

Sudden CardiopulmonaryComplications

Is there anequivalent number of

interventions?

10/15/2016

27

10/15/2016

28

How Do I Lactate Clearance Clinically?

• Be careful with alactemic septic shock

– 25-50% of patients have lactate < 2.0 mmol/L.

• Lactate can be influenced by:

– Inadequate source control, dead bowel

– Inadequate delivery (corrected by ScvO2)

– Overuse of vasopressors

– Liver disease

– Thiamine deficiency, metformin, protease

• Identification

– Suspect infection (SIRS)

• Initiation

• Cultures, Antibiotics

– Source Control

• Risk Stratification

– Fluid challenge

– Lactate (Initial and Repeat)

• Hemodynamic Optimization

– Preload

– Afterload

– Contractility

– Balance DO2 & VO2

• Immunomodulation (steroids)

10/15/2016

29

• Mechanical Ventilation

• Quality Initiatives

• Economics

• Outcome Benefits

• ProCESS, ARISE and ProMISe

• Future of Sepsis Management

The Hemodynamics ofSeptic Shock

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

10/15/2016

30

MAP CVP

Cardiac Index ScvO2

ProCESS,ProMISe

and ARISe

Oxygen Debt: To Pay or Not to Pay

10/15/2016

31

Optimization Trials“A Closer Look”

Mortality

(Boyd, New Horiz, 1996)

Early

Late

(Kern, Crit Care Med, 2002)

10/15/2016

32

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

Importance of the Fluid Challenge

10/15/2016

33

Is Fluid Administration Within Six Hours Early Enough forBetter Patient Outcomes in Sepsis Septic Shock

• Results:– 594 patients, median age was 70 (58-80) years.– Adjusted for chronic co-morbidity, acute illness, age and fluid given in

the first 6 hours.

• In fluids within the first 3 hours:

– Survival at discharge 2085 ml (940-4080)

– Death at discharge 1600 ml (600-3010), p=0.007.– In the latter 3 hours, median was 660 ml (290-1485) vs. 800 ml (360-

1680), p=0.09.

• Earlier fluid resuscitation (within the first 3 hours) reducesmortality. [odds ratio 0.34 (95% CI, 0.15 to 0.75), p=0.008].

Lee, Sarah; Li, Guangxi; Jaffer-Sathick, Insara; Valerio-Rojas, Juan Carlos;Cartin-Ceba, Rodrigo; Kashyap, Rahul, Crit Care Med, 2012

10/15/2016

34

4981

3499

“The earlier fluid resuscitation may account for the lack ofoutcome differences in the trial and may have contributedto the overall low 60-day in-hospital mortality rate of 19%.”

You want to pick a fight?Just mention CVP

10/15/2016

35

Late

Early

999,949

203,481

10/15/2016

36

Early

LateAge-adjusted

hospital mortalitydeclined from

40.4% in 1998 to31.4% in 2009

• 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 (e.coli in blood – 24 hours)• 7 liters of fluid

Does the type of fluid matter?

10/15/2016

37

Severe Sepsis

10/15/2016

38

10/15/2016

39

• In critically ill septic patients manifesting hyperchloremia (Cl=110mEq/L) on ICU admission

• Higher Cl levels and within-subject worsening hyperchloremia at 72hours of ICU stay were associated with all-cause hospital mortality.

• These associations were independent of base deficit, cumulative fluidbalance, acute kidney injury, and other critical illness parameters.

Crit Care Med, 2015

Adjuncts to TitratingFluid Therapy

10/15/2016

40

Vasopressor Therapy

10/15/2016

41

VasopressorTherapy

Duration of Hypotension

10/15/2016

42

March, 2014

10/15/2016

43

The Choice of a Vasopressor

Hypotensive

Tachycardic Patient

Hypotensive

Bradycardic Patient

10/15/2016

44

Early – Ebb PhaseResuscitation

Late – Flow PhaseDe-Resuscitation

Optimal FluidMaintenance

Inadequate Fluid(Hydrophobia)Tissue Hypoxia

Cardiopulmonary EventsInflammationOrgan Failure

Too Much Fluid(Hydrophilia)

Volume OverloadOrgan Failure

Increased Ventilator DaysHemodialysis

Co

mp

licat

ion

s

10/15/2016

45

Complications of Vasopressors

Critical Care Medicine, 2014

• If vasoactive drugs were given in the first hour:

– Higher pressures

– Less fluids were given

• Pharmacologic vasoconstriction and hypovolemia:

– impairs organ perfusion

– increased mortality

• “cold septic shock” is simply hypoperfusion in patients with acirculating volume insufficient to cope with their dilatedcapacitance vessels

10/15/2016

46

Critical Care Medicine, 2014

• Patients become “warm” after administration of adequatevolume of fluids

• These findings support previously shown benefits ofaggressive early fluid resuscitation.

• It may be detrimental to start vasoactive agents withinthe first hour after shock onset.

– Delaying them for at least one hour while the fluid resuscitationis begun.

What do these individuals havein common?

Macrophage

Migration

Inhibition

Factor

(Reichlin, NEJM, 1993)(Chrousos, NEJM, 1995)(Soni, Am J Med, 1995)

(Beishuizen, J Clin Endo & Meb, 2001)

Surgery and

TraumaDrugs

Infection (Sepsis)Intense heat/cold

AdrenalInsufficiency

ContemporaryAdrenal Dysfunction

10/15/2016

47

• The effects of low or high APACHE II score and early or latehydrocortisone initiation are additive (<9 hours).

• High APACHE score (>19), the early initiation ofhydrocortisone increased the survival rate from19.8% to 41.2% (p = 0.021).

• Low APACHE score (< 19), early initiation of hydrocortisoneincreased the survival rate from 55.0% to 83.3%.

10/15/2016

48

14.5% Reductionin Vasopressor

Use if Optimizedwith EGDT

Hold steroid useuntil the patient

has beenresuscitated andendpoints met

(6-8 hours)

CST is optionaland consider a

baseline cortisol

10/15/2016

49

• This was a prospective, multi-centre, observational study conductedover a one-year period in ten French ICUs.

• ScvO2 was measured upon and 6 hours later (H6), by blood sampling.

• More than 25% of septic patients had ScvO2 < 70% in the first hoursafter ICU admission hours after ICU admission..

• 10% higher mortality.

10/15/2016

50

What if my patientis anemic?

NEJM, 2014

NEJM, 2014

10/15/2016

51

NEJM, 2014

Myocardial Suppression andInotropic Therapy

10/15/2016

52

Global TissueHypoxia

InflammatoryMediators

Parillo, JClin.Invest, 1985

Difference in Lactate Levels and Cardiac Function Among Three Septic PatientGroups Stratified By Initial Central Venous Oxygen Saturation Levels

Nakamura, Masataka; Coopersmith, Craig; Greg, Martin; McConnell, Kevin; Kandiah, Prem;Still, Mary; Nicholls, Matthew; Oda, Shigeto; Hirasawa, Hiroyuki; Buchman, Timothy

Critical Care Medicine 2012;40 (12) :1-328

NCardiacDisease

Mortality

Low ScvO2 (<70%) 108 38.7% 41.2%

Normal ScvO2 (70-80%) 119 25.0% 24.1%

High ScvO2 (>80%) 78 16.7% 30.8%

10/15/2016

53

Ms. Peterson

• Infected foot – clostridium Perf (anaerobe)

• Lactate of 10 and oliguric

• BNP -3467

• BUN-77 and creatinine 4.3

• CXR

• Ultrasound

Venous Hyperoxia in Sepsis

Pope, Annals of Emerg Med, 2009

< 70% 70 - 90% > 90%

10/15/2016

54

The Microcirculation

Mechanical Ventilation

10/15/2016

55

Mechanical Ventilation and Sepsis

• Mechanical ventilation rate of 52.4%

• Mortality rates:

–48.3 - mechanically ventilated with ALI

– 45.7 - without acute lung injury

–33.0% - without mechanical ventilation,respectively.

10/15/2016

56

• Reduction in hospital mortality

• Reduction in baro-trauma

• Reduction in ventilator free days

10/15/2016

57

Early versus LateSepsis Care

10/15/2016

58

2011

How can we over comethe constipation in

sepsis management?

Continuous QualityImprovement

StructureProcess

FeedbackEducation

Outcomes

Donabedian A. Continuity and change in the quest for quality.Clin Perform Qual Health Care. 1993;1:9-16.

10/15/2016

59

Sepsis Guidelines Saves Lives

EGDT after a DecadeNEJM, 2001

Mor

tali

ty%

Pre-EGDT Control EGDT

51%

46%

30%

November 8, 2001

20%

2015

10/15/2016

60

JAMA. 2016;315(8):775-787

Before (Control) After (Treatment) Total

Studies/Patient level data N % Mortality SD N % Mortality SD N

Randomized Control (13) 2776 46.36 20 2831 36.0 15 5607

Quasi experimental (4) 379 45.78 12 741 28.5 12 1120

Prospective observational (33) 25945 40.03 11 36315 26.7 11 62260

Prospective with historical controls (9) 957 45.51 13 1293 29.6 12 2250

Retrospective (19) 1050 41.15 13 1133 24.7 9 2183

Summary of All Studies 31107 42.47 14 42313 28.7 12 73420

10/15/2016

61

March 6, 2013

Joint Commission CMS AHRQ

1. Measure lactate

2. Blood cultures/appropriate cultures

3. Give broad spectrum antibiotics

4. Fluid Challenge of 30 cc/ kg if (hypotension/lactate > 4mM/L)

3H

our

Bu

nd

le6

Ho

ur

Bu

nd

le

5. If persistent hypotension– vasopressor to maintain MAP > 65 mmHg

6. Document perfusion:

7. Re-measure lactate within 6 hours

InvasiveCVP

ScvO2

UltrasoundIVCTEETTE

Dynamic Assessment ofVolume Responsivenessto Fluid Challenge or PLR

SVVSLR

Bioimpedence

Physical ExamPeripheral

PulsesCapillary Refill

(<2 secs)Skin Turgor

• Identification

– Suspect infection (SIRS)

• Initiation (8%)

– Cultures, Antibiotics (6%)

– Source Control (2-16%)

• Risk Stratification

– Fluid challenge (3-5%)

– Lactate (10-12%)

• Hem. Optimization (9-10.4%)

– Preload (CVP)

– Afterload

– Contractility

– Balance DO2 & VO2

• Immunomodulation (8%)