severe sepsis & septic shock objectives - ucsf cme · severe sepsis & septic shock ... door...

1

Sepsis: the 1st 6 hoursIdentification

&Initial Management

Chris Fee, MDUCSF Division of Emergency Medicine

2007 Topics in Emergency Medicine

Severe Sepsis & Septic Shock

• Gain respect for severe sepsis/septic shock

• Utilize lactate to identify high risk patients & monitor resuscitation

• Understand & implement the 6 hour sepsis bundle

Objectives

What would you do?Case #1

• 66 yo man presents with anterior CP


• 19 yo woman with abdominal pain after a motor vehicle collision

HR 120, BP 80/50

After 1.5 L NS IV

HR 90, BP 126/76


• 66 yo woman with R weakness & aphasia


• 58 yo man with cough, fever, SOB

T 38.3 °C

HR 106

BP 110/62

RR 22

O2 sat 98% on 4L/min

Lactate 4.4 mmol/L

2

Cases: Common Themes

• 1. Acute anterior wall STEMI

• 2. Isolated blunt abdominal trauma

• 3. Acute ischemic L MCA CVA

• 4. Severe sepsis due to community acquired pneumonia

Door to lytics (30 mins)/balloon time (90 mins)

“Golden Hour of Trauma”

3 Hour window for lytics

Mortality10%

8%

10%

30%6 Hour Sepsis Bundle of CareAntibiotics within 4 Hours???

Now what would you do?Case #4 (same but different)

• 58 yo man with cough, fever, SOB

T 38.3 °C

HR 126

BP 60/46

RR 22

O2 sat 98% on 4L/min

76/522L NS IV

Septic Shock

Outline

• Surviving Sepsis CampaignDefinitions & EpidemiologyEvidence-Based RecommendationsImplementation strategies

• Controversies• Future Directions

Dellinger RP, et al. Intensive Care Med. 2004;30:536-555.Osborn TM, et al. Ann Emerg Med 2005;46:228-31.



SIRS

Systemic Inflammatory Response Syndrome (SIRS) (≥2)•T > 38 °C or < 36 °C•HR > 90•RR > 20 or PaCO2 < 32mmHg•WBC > 12, < 4, or > 10% bands

Pancreatitis

Trauma

Burns

Other

Infection

Sepsis

Severe Sepsis

Sepsis + ≥ 1 organ dysfunction orlactate ≥ 4mmol/L

Bone RC, et al. Chest 1992:1644-55. Vincent JL. Crit Care Med 1997;25:372-4.

Septic Shock

Sepsis + hypotension (after 20mL/kg IVF)

Organ Dysfunction

• CardiovascularSBP< 90 mmHgMAP< 65SBP decrease > 40 mmHg from baseline

• RenalCreatinine > 2UOP < 0.5ml/kg/hr for > 2 hrs

• HemePlatelets < 100,000

• MetabolicLactate > 2.0 once CVP > 8-12 mmHg

• RespiratoryBilateral pulmonary infiltrates with

a new (or increased) O2 requirement to maintain SpO2>90%PaO2/FiO2 <300

• HepaticINR > 1.5aPTT > 60 secsTotal bili > 2 mg/dL

***At least 7 different definitions***

www.survivingsepsis.org

3

Pathogenesis

Organism

Global Tissue Hypoxia & Organ Dysfunction

Severe Sepsis

Multiple Organ Dysfunction & Refractory Hypotension

Septic Shock

Systemic Inflammation or Inflammatory Response

Diffuse Endothelial Disruption & Microcirculation Defects

Nguyen HB, et al. Ann Emerg Med 2006;48:28-54.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Death

Pathogenesis



Death

Organism

Global Tissue Hypoxia & Organ Dysfunction

Severe Sepsis

Multiple Organ Dysfunction & Refractory Hypotension

Septic Shock

Systemic Inflammation or Inflammatory Response

Diffuse Endothelial Disruption & Microcirculation Defects

Nguyen HB, et al. Ann Emerg Med 2006;48:28-54.

How many patients with severe sepsis/septic shock are seen in your workplace each year?

A. <5B. 6-10C. 11-15D. 16-20E. >20

Incidence of Severe SepsisC

ases

/100

,000

300

250

200

150

100

50

0AIDS* Colon

CA§Breast CA§

CHF† Severe Sepsis‡

*Karon JM, et al. Am J Public Health. 2001;91:1060-1068 §American Cancer Society, 2001‡Angus, et al. Crit Care Med. 2001;29:1303-10 †American Heart Association, 2001

Mortality of Severe Sepsis

250,000

200,000

150,000

100,000

50,000

0

Dea

ths/

Yea

r

AIDS* Breast CA§

Acute MI†

Severe Sepsis‡

*Karon JM, et al. Am J Public Health. 2001;91:1060-1068 §American Cancer Society, 2001‡Angus, et al. Crit Care Med. 2001;29:1303-10 †American Heart Association, 2001

Probability of Death

Days in Hospital

60%

40%

20%

0%

0 20 40 60 80

Mor

talit

y

Alberti C, et al. AJRCCM 2003;168:77-84.

Infection no SIRS (n=584)

Sepsis (n=1063)

Severe Sepsis (n=827)

Septic Shock (n=1134)



4

Severe Sepsis-Associated Mortality

Angus

0%

20%

40%

60%

80%

Mor

talit

y

Number of Dysfunctional Organ Systems

Vincent

One Two Three ≥ Four

Vincent JL, et al. Crit Care Med 1988;21:1793-800. Angus DC, et al. Crit Care Med 2001;29:1303-10.

Newer Diagnostic Criteriafor Sepsis

• General variablesTemp > 38.3 or < 36CHR > 90TachypneaAltered mental statusSignificant edema or positive fluid balance (>20ml/kg/24hrs)Glucose > 120 (no DM)

• Inflammatory variablesWBC >12 or < 4 or > 10% bandsCRP > 2 SD above normalProcalcitonin > 2 SD above normal

• Hemodynamic variablesSBP < 90, MAP < 70 or SBP decrease > 40SvO2 < 70%Cardiac index > 3.5 L/min/m2

• Organ Dysfunction variablesPaO2/FiO2 < 300Acute oliguriaCreatinine increase > 0.5INR > 1.5 or aPTT > 60sIleusPlatelets < 100,000Total bilirubin > 4

• Tissue perfusion variablesHyperlactatemiaDecreased cap refill or mottling

Infection (documented or suspected) and SOME of the following:

Levy MM, et al. Crit Care Med2003;31:1250-6.



Identification(2 Step Process)

• Step 1. Is the patient septic?≥2 SIRS criteria + suspected infection

Step 2. Does the patient have severe sepsis/septic shock?

Any one of the following:1. Persistent hypotension (after 20mL/kg IVF)2. 1 or more organ system dysfunction3. Lactate > 4mmol/L Why???

Do You Currently Order Lactate Levels on Patients with Suspected Sepsis?

A. YesB. No, it’s not going to change my

managementC. No, the lab turnaround makes it

essentially useless to meD. No, it’s not available where I workE. No, other reason

Lactate

Mor

talit

y R

ate

0%

5%

10%

15%

20%

25%

0 - 2.4 2.4 – 3.9 ≥ 4

Death within 3 days28-day in-hospital mortality

Shapiro N, et al. Ann Emerg Med 2005;45:524-8.

5

Lactate“Cryptic Shock”

• Tissue hypoperfusion without hypotension

• On the brink of cardiovascular collapse↓ Myocardial contractility & complianceIf not treated aggressively, leads to multiple organ failure & mortality

LactateResuscitation

• Lactate clearance inversely related to mortality (measured at 6 hrs from initiation)

• Best available marker for need of ongoing resuscitation



Nguyen HB, et al. Crit Care Med 2004;32:1637-42.

So You Can Identify Severe Sepsis/Septic Shock, Now What?

• Step 3Source controlEarly cultures & antibioticsEarly goal-directed therapyProtective ventilation strategiesActivated protein CIntensive insulin therapyLow dose steroidsNarrowing antibiotic spectrum once sensitivities available

Grade of Recommendation

BBD

C/E?

E

ED&E

BED

ICU

Early Goal-Directed Therapy

Physical exam, vitals, urine output, CVP, mental status are

UNRELIABLE indicators of perfusion


• Inadequate O2 delivery = key to progressionSurrogate measure of cardiac output & oxygen extraction at the tissue level

Mixed venous (SvO2) and central venous (ScvO2) O2 saturation

• Manipulate preload, afterload, contractility Goal: balance O2 demand & delivery

Rivers E, et al. NEJM 2001;345:1368-77.


Sedation, paralysis (if intubated), or both

Central venous ±arterial catheterization

1. SIRS + suspected infection &

2. SBP < 90 (after 20mL/kg IVF) or lactate ≥ 4 or multiorgan

dysfunction

Supplemental O2 ±endotracheal intubation &

mechanical ventilation


6


CVPColloid

<8 mm HgCrystalloid

8-12 mm Hg





dysfunction





MAP

CVPColloid

<8 mm HgCrystalloid

8-12 mm Hg





dysfunction



Vasoactive agents<65 mm Hg>90 mm Hg

Norepinephrine pressor of choice


>65 and <90 mm Hg


ScvO2Transfusion of red cells until hematocrit > 30%

<70%≥ 70%


CVPColloid

<8 mm HgCrystalloid

8-12 mm Hg




dysfunction



MAP

>65 and <90 mm Hg



<70%≥ 70%

Inotropic agentsDobutamine




CVPColloid

<8 mm HgCrystalloid

8-12 mm Hg




dysfunction



MAP

>65 and <90 mm Hg



ScvO2Transfusion of red cells until hematocrit > 30%

<70%≥ 70%

<70%≥ 70%



Goals achieved?

No

Hospital admission

Yes




CVP

MAP

ScvO2

Goals achieved?

Colloid

<8 mm HgCrystalloid

8-12 mm Hg

>65 and <90 mm HgTransfusion of red cells until hematocrit > 30%

<70%≥ 70%

No

Hospital admission

Yes



dysfunction





<70%≥ 70%




• ↓ In-hospital mortality 16%46.5% controls vs 30.5% in EGDT group

Relative risk of death = 0.58


7

Does Your ED/Practice Currently Utilize an EGDT Protocol?

A. YesB. No, lack of specialized monitoring

equipmentC. No, too many ED resources requiredD. No, need for central venous cannulationE. No, other reason(s)



Concept of the “Bundle”

• Institute for Healthcare Improvement (www.ihi.org)

Bundle: group of interventions that, when implemented together, result in better outcomes than individually

Institute for Healthcare Improvement website: as accessed on 9/2/2007.

Concept of the “Bundle”The Acute MI Model

Angiotensin-converting enzyme (ACE) inhibitors, lipid-lowering agents (statins), additional antihypertensive agents

Secondary prevention strategies

Percutaneous transluminal coronary angioplasty (PTCA), stenting, coronary artery bypass grafting (CABG)

Invasive procedures for tissue reperfusion and vessel revascularization

Angiography, intravascular ultrasound, vascular catheterization

Invasive procedures for diagnosis/monitoring

ASA, glycoprotein (GP) IIb/IIIa inhibitors, adenosine diphosphate-(ADP) receptor blockers

Antiplatelet therapies

Heparin, low-molecular-weight heparinsAnticoagulants

Streptokinase, urokinase, alteplase, retaplase, tissue plasminogen activator (tPA)

Fibrinolytics

EchocardiographyCardiac monitoring

Nitrates, analgesics (opioids), oxygen therapy, fluid resuscitation

Acute management

www.survivingsepsis.org

6 Hour (Resuscitation) BundleSteps 1-3 (ED Care)

• Prompt identificationIncludes lactate measurement

• Early cultures & appropriate antibiotics

• EGDTIncludes measurement of CVP & ScvO2

Severe sepsis (2001-2004): 2/3 present via EDAverage ED length of stay: 4.7 hours (20% spent >6 hours)

Which Antibiotics to Give?

Carbapenem + vancomycin or third- or fourth-generation cephalosporin, piperacillin/tazobactam, or ticarcillin/clavulonate + gentamicin

UnknownVancomycinCatheter

Piperacillin/tazobactam or ticarcillin/clavulonate or carbapenem or ampicillin + gentamicin or fluorquinolone

Urinary tract

Carbapenem or ampicillin + metronidazole + gentamicin/tobramycin or fluoroquinolone

Abdomen

Carapenem +/- fluoroquinolone or Cefepime or piperacillin/tazobactam +/- fluoroquinolone

Health care-associated pneumonia

3rd generation cephalosporin + azithromycin or fluoroquinolone

Community-acquired pneumonia

AntibioticSource

54%

20%

10%

8

24 Hour (Management) BundleThe 4th Step (ICU Care)…

• Source control

• Protective ventilation strategies

• Low dose steroids (???)

• Intensive insulin therapy (???)

• Activated protein C (???)

• Narrowing of antibiotic spectrum

Example Sepsis Bundles

♦ MUST (Multiple Urgent Sepsis Therapies)

♦ www.mustprotocol.com

♦ STOP (Strategies to Timely Obviate the

Progression of Sepsis in the ED)

♦ www.llu.edu//llumc/emergency/patientcare

♦ UCSF

♦ Included with syllabus

Strategies for Initiating EGDT

• ED-based

Henry Ford Hospital, MUST protocol

• Rapid response team-based

Good Samaritan Hospital (community)

• ICU-based

UCSF

If you do utilize EGDT, what model do you use?

A. ED-basedB. Rapid Response Team-basedC. ICU-basedD. Not sureE. Don’t utilize EGDT where I work



n





9

ControversiesLactate & “Cryptic Shock”

• Subgroup in River’s EGDT study20% (EGDT) vs 60.9% (control) mortality

• MUST Protocol Implementation37/116 in protocol had “cryptic shock”

Donnino MW. Chest 2003;90S.Shapiro NI, et al. Crit Care Med 2006;34:1025-1032.

ControversiesWhen to Order a Lactate?

• “Blood culture = lactate”

• ≥2 SIRS criteria & suspected infection (i.e. septic)

ControversiesEGDT

1st 6 Hours – Was it the volume?

3.5±2.4L

18.5%

60%

0.8%

Control

EGDT

P<0.001

P<0.001

P<0.001P<0.0015±3L

64%

95%13.7%

Fluids Red Cell Transfusion

Dobutamine ScvO2 ≥ 70%

Rivers E, et al. NEJM 2001;345:1368-77. (see accompanying Letters to the Editor. NEJM 2002;346:1025-1026.)

ControversiesEGDT


CVP

MAP

ScvO2

Goals achieved

Colloid

<8 mm HgCrystalloid

Transfusion of red cells until hematocrit > 30%

<70%≥ 70%

No





<70%



CVP

Dobutamine-induced

hypotension vs unmasks volume

depletion 35.9%

50.4%

13.7%

27.4%

ControversiesEGDT

1st 6 Hours – Was it the volume?

3.5±2.4L

18.5%

60%

0.8%

Control

EGDT

P<0.001

P<0.001

P<0.001P<0.0015±3L

64%

95%13.7%

Fluids Red Cell Transfusion

Dobutamine ScvO2 ≥ 70%

ControversiesStandardized Order Sets

• Cookbook or evidence-based medicine??

• Significantly reduced mortality & length of stay

Micek ST, et al. Crit Care Med 2006;34:2707.

10

ControversiesSingle Center & Small n

• Review of all published EGDT data12 trials (1298 patients)

Aggregate risk reduction of 20.3%

Did not use formal methods for meta-analyses

Otero RM, et al. Chest 2006 Nov;130:1579-95.

ControversiesHigh Cost / Resource Utilization

• 23.4% reduction in hospital costs

• Most cost effective if >16 patients/year

• True for all models (ED-, Rapid Response Team-, and ICU-based care)

Huang DT, et al. Crit Care 2003;7(suppl):S116.

ControversiesProprietary Equipment

• PreSep catheter & Vigilance monitor (Edwards Lifesciences)

• Can use central line (in RA) & drawblood gases for serial ScvO2 levels instead

ControversiesPharma Support of SSC Guidelines

• Lilly & Edwards funded Surviving Sepsis Campaign

? overstated benefits of activated protein CNo mention of ADDRESS/RESOLVE trial data

• Guidelines from other unbiased sourcesare similar

Eichacker PO, Natanson C, Danner RL. NEJM 2006;355:1640-2.



Future DirectionsDiagnostics

• More specific markers for bacterial sepsisProcalcitonin???Soluble Flt-1???

• Predicting who may progress from severe sepsis to septic shock

Heart rate variability

11

Future DirectionsCase #4 (same but more different)

• 58 yo man with cough, fever, SOB.

Lactate 4.4 mmol/L

T 38.3 °C

HR 106

BP 110/62

RR 22

O2 sat 98% on 4L/min via NC




• Blood/urine/CSF cultures negative• 3 days in ICU with broad-spectrum

antibiotics• Clostridium dificile colitis• Rash• $$$• Influenza A positive nasal wash


• Identification of bacteria causing severe sepsis/septic shock in patients using a 16S microarray

10ml bloodCompares rDNA in sample to microarray of rDNA from known bacteria (internal library)In theory: obtain rapid speciation of anybacteria in the bloodstream




Future DirectionsRefinements to EGDT?



CVP

MAP

ScvO2

Goals achieved

Colloid

<8 mm HgCrystalloid

8-12 mm Hg

>65 and <90 mm HgTransfusion of red cells until hematocrit > 30%

<70%≥ 70%

No





<70%≥ 70%


Future DirectionsTreatments

• Statins• Drugs designed against superantigen &

mannose• Inhibition of tissue factor• Interferon gamma to boost macrophage

function• Apoptosis inhibition

12

Mortality Reductions: Sepsis vs. Acute Coronary Syndromes

Abs

olut

e M

orta

lity

Red

uctio

n

16%

12%

8%

4%

0%

Cardiology Trials

Sepsis Trials

GP IIb/II

Ia inh

ibitor

s

Strepto

kinase

in M

I

APC, all c

omers

APC, APACHE II

> 25

EGDT

Low do

se ste

roids

ARDSnet v

ent

Tight g

lycem

ic co

ntrol

Antibio

tics

(< 4 hrs

for p

neumon

ia)

51>100

16

1011

29

6

8

NNT to prevent 1 death

Agarwal R, Singh N. Acad Emerg Med. 2005;12:912.

166

Long Way To Go…

• 2004 survey of academic EDs in 18 states7% reported use of EGDTBarriers

75%: lack of specialized monitoring equipment43%: too many ED resources required36%: need for central venous cannulation

Jones AE, Kline JA. Crit Care Med 2005;33:1888-9.

Take Home Points

• Early identification paramountSIRS criteria, lactate levels

• Concept of “cryptic shock”“Blood culture = lactate”

• Establish sepsis bundles of care in your workplace

Physician champion, interdepartmental/multidisciplinary collaboration

Thank You

• Any Questions?

UCSF Sepsis BundleStep 1: Recognize Sepsis

TIME

0 hoursTriage:

1. Vital Signs (Temp, HR, RR, BP)2. History of Illness

If ≥ 2 SIRS criteria:1. Temp > 38.3C or <36.0C2. HR > 903. RR > 20 or PaCO2<32mmHg4. WBC >12K, <4K or > 10% bands ANDSuspected Bacterial Infection

ED RN: if obtaining blood cultures prior to pt seen by MD, send CBC c diff and

lactate level or discuss with Attending

If < 2 SIRS or no Suspected Bacterial Infection

NOT SEPTIC

EXIT PROTOCOL

NOW!

UCSF Sepsis BundleStep 2: Assess for Severe Sepsis/Shock

Assess appropriateness of EGDT:1. Obtain WBC2. Obtain VBG, lactate, electrolytes3. Administer fluid bolus4. Obtain appropriate cultures5. Assess organ function6. Initiate antibiotic therapy

2 hours

4 hours

If SBP, lactate, organ function within normal limits

NOT SEVERE SEPSIS/ SEPTIC SHOCKReassess in 1 hour If one or more of:

1. SBP < 90 after 20mL/kg fluid administration2. Lactate ≥4mmol/L3. ≥ 1 organ dysfunction*

PATIENT HAS SEVERE SEPSIS/SEPTIC SHOCK:1. CONSULT ICU FELLOW r.e. EGDT2. MOVE PATIENT TO ICU, IF POSSIBLE3. INITIATE EARLY GOAL DIRECTED THERAPY

13

4 hours Initiate Early Goal Directed Therapy Orders:1. Place central line for CVP/ScvO2 monitoring2. Begin broad spectrum antibiotics

CVP? If < 8mmHg 500mL crystalloid bolus over 30 min

If≥8

MAP? If < 65mmHg Titratevasopressors**

ScvO2? If < 70% Hgb?

If ≥65

6-8 hours

If ≥

70%

EARLY GOAL DIRECTED THERAPY TARGETS ACHIEVED:

1.) REASSESS ANTIBIOTIC THERAPY2.) CONSIDER ADDITIONAL THERAPIES3.) IF ScvO2 STILL < 70%, CONSIDER INTUBATION, MECHANICAL VENTILATION, PARALYSIS, AND SEDATION TO DECREASE O2 CONSUMPTION

If ≥10

Titrateinotropic agent

If < 10mg/dL Transfuse

UCSF Sepsis BundleStep 4: ICU Care

1.) ASSESS PATIENT FOR APPROPRIATENESS OF ADDITIONAL THERAPIES#

Calculate APACHE II score

Measure rise incortisol after ACTH-stim test***

Measure blood glucose

Assess for ALI or ARDS

If≥

25

Give APC

If < 9mcg/dL

Give Steroids

If ≥140 mg/dL

Maintain serum glucose btwn80-120mg/dL

Ifresp. failure

Ventilate with low tidal volume protective mechanical ventilation

Selected References

• Surviving Sepsis CampaignDellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858-873.Osborn TM, Nguyen HB, Rivers EP. Emergency medicine and the Surviving Sepsis Campaign: an international approach to managing severe sepsis and septic shock. Ann Emerg Med 2005;46:228-31.www.survivingsepsis.org

• Early Goal-Directed TherapyRivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM 2001;345:1368-77.

Accompanying Letters to the Editor. NEJM 2002;346:1025-1026.• Treatment Bundles

www.ihi.org (Institute for Healthcare Improvement)www.mustprotocol.comwww.llu.edu//llumc/emergency/patientcare

• ReviewNguyen HB, Rivers EP, Abrahamian FM, et al. Severe sepsis and septic shock: review of the literature and emergency department management guidelines. Ann Emerg Med 2006;48:28-54.Otero RM, Nguyen HB, Huang DT, et al. Early goal-directed therapy in severe sepsis and septic shock revisited: concepts, controversies, and contemporary findings. Chest 2006 Nov;130:1579-95.Russell JA. Management of sepsis. NEJM 2006;355:1699-42.

Accompanying Letters to the Editor. NEJM 2007;356:1178-82.

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