Urgent Matters Webinar Series

Improving Sepsis Care in Emergency Department

September 22, 2015

Information Release Date: May 5, 2015

Termination Date: May 5, 2016

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The George Washington University School of Medicine and Health Sciences is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The George Washington University School of Medicine and Health Sciences designates this live internet activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Instructions for Obtaining Credit

At the end of this webinar, you will receive an email for completing the online course evaluation. Your certificate of credit will be available immediately after you complete the evaluation.

Information In accordance with the Accreditation Council for Continuing Medical Education's Standards for Commercial Support, The George Washington University Office of C ontinuing Education in the Health Professions (CEHP) requires that all individuals involved in the development and presentation of CME activity content disclose any relevant financial relationships with commercial interest(s). CEHP identifies and resolves all conflicts of interest prior to an individual’s participation in an educational activity

The following faculty, planners, and staff report that they have nor relevant financial relationships with commercial interest(s):

David Gaieski (Speaker) JessePines (Course Director) Danielle Lazar (Staff)

Molly Benoit (Staff)

LeticiaHall(Staff)

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Thank You For Participating!

The George Washington University School of Medicine and Health Sciences is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The George Washington University School of Medicine and Health Sciences designates this live internet activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

You will receive an email with an evaluation following this program, when you complete this evaluation you will be taken to a website with instructions for claiming your CME.

This program was recorded and will be posted on the Urgent Matters Website with the slides

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FOLLOW URGENT MATTERS

Sepsis:

“What’s the problem?

What’s the solution?”

David F. Gaieski, MD, FACEP Associate Professor, Department of Emergency Medicine

Vice Chair for Resuscitation Services Director of Emergency Critical Care

Sidney Kimmel Medical College Thomas Jefferson University

September 22th, 2015

Disclosures

• Bard Medical Division—research

funding to investigate temperature

burden in patients with severe sepsis

• No other relevant sepsis-related

disclosures

Outline

• SEP-1: Overview

• A case: Initial Presentation

• The Continuum of Sepsis

• Our case: Changing Severity

• Goals of Resuscitation

• Epidemiology of Sepsis

Outline (continued)

• EGDT

• Need for Early Recognition: – SIRS, Lactate, Time to Antibiotics

• Modifying EGDT: Protocolized Care in 2015

• Preventing Readmissions

• Case: Conclusion

“Except on few occasions, the

patient appears to die from the

body’s response to infection rather

than from…[the infection itself….]”

Sir William Osler, 1904

SEP-1: Overview

SEP-1

• Not a talk about implementing SEP-1

• Goal: Efficient, effective, timely care

• Acknowledges “burden of severe sepsis”

• If 2 SIRS, infection, organ dysfxn, then…

• 3 Hour Goals

– Lactate, blood cultures, antibiotics, fluid

• 6 Hour Goals

– Repeat lactate, vasopressors, assessment of

volume status, tissue perfusion

A Case: Initial Presentation

Case Vignette

• 54 year-old male

• PMHx: HTN, PAF, HL, and OA

• Chief complaint: abdominal pain

• Began 3 days ago after eating dinner, stuttering since then, becoming more severe/constant about 6 hours before presentation

• Fever to 101.5°F, 4 hours prior, treated w/ acetaminophen; two days nausea; one episode of vomiting earlier today

Case Vignette

• Allergies: NKDA

• Medications: ASA, metoprolol, amlodipine, simivastatin

• Triage VS: Tº, 100.5°F; BP, 128/78 mm Hg; HR, 88 beats per minute; RR, 21 breaths per minute; and O2 sat, 96% on RA; pain, 6/10

• Triaged as ESI 3 patient, and asked to wait in the waiting room along with 15 other patients waiting to be seen

Our patient. Next steps?

• Patient waits to be seen

• Other easily obtainable data that could help clarify the urgency of initiating treatment?

• What if serum lactate is 1.4 mmol/L?

• What if it is 4.1 mmol/L?

• EMR algorithm utilizes CC + VS to generate an automatic order for a serum lactate

• Drawn by EMT 10 minutes after triage

• Sent to the critical care laboratory for analysis

Challenge of sepsis patients

• This is a typical sepsis patient

• Why sepsis? – Presumed infection (likely intra-abdominal process) +

inflammatory response (fever, tachypnea)

• Challenge for clinicians: – How sick is he?

– Does he have a time-sensitive infection?

– How aggressive does his treatment need to be?

• On initial presentation: – no obvious signs of end organ dysfunction

– Does not obviously have severe sepsis

– What does this mean?

The Continuum of Sepsis

The Continuum of Sepsis

Sepsis SIRS Severe Sepsis Septic Shock

The Continuum of Sepsis

Sepsis SIRS Severe Sepsis Septic Shock

The Continuum of Sepsis

Sepsis SIRS Severe Sepsis Septic Shock

The Continuum of Sepsis

Sepsis SIRS Severe Sepsis Septic Shock

The Continuum of Sepsis

Bone et al. Chest 1992

Sepsis SIRS Severe Sepsis

Systemic Inflammatory Response Syndrome

SIRS criteria

• Temp < 96.8° or > 100.4° F

• HR > 90

• RR > 20 or PCO2 < 32

• WBC < 4 or > 12 or bands > 10%

Septic Shock

The Continuum of Sepsis

Sepsis SIRS Severe Sepsis Septic Shock

Systemic Inflammatory Response to Infection

• Suspected or confirmed infection

• 2 or more SIRS criteria

Bone et al. Chest 1992

The Continuum of Sepsis

Sepsis SIRS Severe Sepsis Septic Shock

Sepsis plus Organ Dysfunction

• Elevated Creatinine

• Elevated INR

• Altered Mental Status

• Elevated Lactate

• Hypotension that responds to fluid

Levy et al. Crit Care Med; 2003

The Continuum of Sepsis

Sepsis SIRS Severe Sepsis Septic Shock

Severe Sepsis and Hypotension

• Hypotension that does NOT respond to fluid (30 cc/kg bolus)

Bone et al. Chest, 1992

Rivers et al. NEJM, 2001

Cryptic Shock

•Normotensive

•Lactate > 4

Our Case: Changing Severity

Patient Vignette

• Lactate (15 minutes after sent)= 5.4 mmol/L

• Immediately brought back to a treatment room

• 2 18 gauge IVs placed

• 3 L NSS were infused in 1 hr

• WBC=16.5; HCO3-=18; Tbili=2.7; Alk phos=235; AST/ALT 335/284; lipase 650

Patient Vignette

• Repeat VS: BP 128/82; HR 84; RR 24

• Bedside ultrasound: – Gallstones

– GBWT

– Dilated intrahepatic ducts

• Bedside ECHO: – Under-filled RV

– > 50% IVC collapse

• Continue volume resuscitation

• Close monitoring

Goals of Resuscitation

Initial Management

IV access

Fluid resuscitation

Supplemental oxygen

Cardiac monitoring

Labs, cultures, CXR

Antibiotics

Is the patient in shock?

Goals of Interventions for Shock

• Stabilize patient

• Eradicate source of infection

• Restore perfusion

• Modulate body’s inflammatory and

anti-inflammatory responses

• Cessation of ongoing lactate

production

Epidemiology of Sepsis

Why is this so Important?

• A patient a minute presents to a US ED

• 750,000 cases/yr of severe sepsis in USA

• 215,000 deaths/yr directly related to sepsis

• Tenth leading cause of death in USA

• Rate of sepsis cases is increasing faster than the population

• 37% of severe sepsis patients come through the ED

Wang et al. Crit Care Med, 2007

Angus et al. Crit Care Med, 2001

Underestimate?

• “Benchmarking the incidence and mortality of

severe sepsis in the United States”

• NIS: Nationally representative sample

• 4 previously validated capture techniques

(Angus, Wang, Dobrovskii, Martin)

• All utilize ICD 9 codes (+/- sepsis codes)

• Annual incidence and mortality from severe

sepsis

Gaieski et al, CCM, 2013

Gaieski et al, CCM, 2013

Gaieski et al, CCM, 2013

Kaukonen, JAMA, 2014

Early Goal-Directed Therapy

Negative Trials in the 80s and 90s

• High dose methylprednisolone

• NSAIDs

• Anti-LPS

• TNF receptor antagonists

• GOT

• Shared features: – ICU initiated

– 24 hours or more to enrollment

– Non-selective interventions

A new approach was needed…

Critical Care

• Critical care is a concept

not a location

• It is a way of treating patients that

begins in the pre-hospital setting with

EMS care, continues in the ED, and is

completed in the ICU

Safar P. Critical care medicine---quo vadis? CCM. 1974;2:1-5

Early Goal-Directed Therapy

(EGDT)

Rivers et al. NEJM, 2001

Algorithmic

EGDT Mortality

46.5%

30.5%

49.0%

33.3%

56.9%

44.3%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

In House 28-Day 60-Day

Standard

EGDT

Rivers et al NEJM, 2001

Need for Early Recognition

Systemic Inflammatory Response System

(SIRS) Criteria

Breaking down initial detection

• How helpful are the SIRS criteria?

3

710

17 16

20

46

0

10

20

30

40

50

No SIRS SIRS 2 SIRS 3 SIRS 4 Sepsis Severe

Sepsis

Septic

Shock

RANGEL-FRAUSTO JAMA 1995

Mort

alit

y, %

Mortality in Admitted Patients

SIRS, Severe Sepsis

• Historically, SIRS=>very sensitive; but not

specific

• Shapiro: SIRS neither sensitive nor specific

• 3102 pts, suspected infection (blood culture

drawn) – 34% (420/1219) severe sepsis pts didn’t meet SIRS criteria

– 24% (13/54) septic shock pts didn’t meet SIRS criteria

Shapiro et al, Ann Emerg Med 2006

• 172 ICUs in Australia, New Zealand

• 109,663 severe sepsis patients

– 87.9% SIRS-positive

– 12.1% SIRS-negative

• “The need for two or more SIRS

criteria…excluded one in eight otherwise

similar patients with infection, organ failure,

and substantial mortality…”

Kaukonen et al. NEJM, 2015

Kaukonen et al. NEJM, 2015

Lactate

Utilizing Lactate

Liver: Cori Cycle

PDH

Thiamine

Lactate Production

X

Cori

Cycle

• Hypothesis

– Lactate measured on ED presentation is associated with mortality and risk stratifies severe sepsis patients INDEPENDENT of blood pressure

• 831/856 (97%) of admitted severe sepsis pts had lactate sent

– Median lactate=2.9 mmol/L

– 28 day mortality: 22.7%

• Divided into:

– Low: ≤ 2mmol/L

– Medium: > 2 to ≤ 3.9mmol/L

– High: ≥ 4mmol/L

• Stratified to presence or absence of refractory hypotension

Mikkelsen et al. Crit Care Med, 2009

ED Lactate in Severe Sepsis

Lactate (mmol/L)

Mo

rta

lity (

%)

Mikkelsen et al. CCM. 2009

ED Lactate in Severe Sepsis

Lactate (mmol/L)

Mo

rta

lity (

%)

Mikkelsen et al. CCM. 2009

Patient Vignette (cont’d)

• A-line placed in L femoral artery

• CVC placed in the R IJ vein under ultrasound guidance – initial CVP: 6 mmHg, MAP: 55 mmHg, initial

ScvO2: 38%

• Further fluid boluses

• After 4 L NSS was infused – CVP: 12 mmHg

– MAP: 59 mmHg

– ScvO2: 45%

Patient Vignette (cont’d)

• Input: 4550cc; Output 20cc

• Repeat ECHO: – Decreased contractility, EF 45%

– IVC collapse decreased

• Started on norepinephrine and dobutamine

• Given Vancomycin and Piperacillin-Tazobactam with 1st antibiotic started 50 minutes after triage

Does that matter?

Time to Antibiotics

Time to Antibiotics

• Design – Retrospective cohort study of 14 ICUs

• Patients – 2,731 adults with septic shock

• Primary variable – Duration of hypotension prior to administration

of appropriate antimicrobial

• Primary outcome measure – Survival to hospital discharge

Kumar et al. Critical Care Medicine. 2006

Time to Antibiotic

0

10

20

30

40

50

60

70

Time 0 1 hour 2 hours 3 hours 4 hours 5 hours 6 hours

Time to Antibiotic

Mo

rta

lity

7.6% absolute increase in mortality per hour

Kumar et al. Critical Care Medicine, 2006

• To study the relationship between time to antibiotics and mortality in patients treated with EGDT in the ED

• 261 patients

• Average time to antibiotics:

– Triage to antibiotics: 119 minutes

– Qualification for EGDT to antibiotics: 42 minutes

Gaieski et al. Crit Care Med, 2010

Time Qual for EGDT to

Appropriate Antibiotics

0

5

10

15

20

25

30

35

40

45

< 1 hour < 2 hour < 3 hour

25.2

28.4 28.7

38.6 40.4

44.7

Inp

ati

en

t M

ort

alit

y (

%)

Antibiotic Timing

Goal Delayed

Gaieski et al. CCM, 2010

Broad-Spectrum Antimicrobials:

+ Cefepime 1 gm IV (1)

+ Vancomycin 1 gm (≤ 70 kg) or

1.5 gm (> 70 kg) IV

± Amikacin 15 mg/kg or

7.5 mg/kg (CrCl < 20) IV (4)

PCN

Allergy

Broad-Spectrum Antimicrobials:

+ Levofloxacin 750 mg IV

+ Vancomycin 1 gm (≤ 70 kg) or

1.5 gm (> 70 kg) IV

± Amikacin 15 mg/kg or

7.5 mg/kg (CrCl < 20) IV (4)

Community Acquired Pneumonia: + Azithromycin 500mg IV (2)

Anaerobic Source: + Metronidazole 500 mg IV (3)

On TPN: + Fluconazole 400 mg IV

Prolonged Neutropenia ±

Steroids:

+ Caspofungin 70 mg IV

± Hydrocortisone 50-100 mg IV

Yes No

Gaieski et al. CCM, 2011

Modifying EGDT

• Protocol-driven sepsis care lowers mortality

• EGDT underutilized

• What factors are associated with not initiating

EGDT in ED?

• 340 EGDT-eligible patients

• EGDT not initiated in 142 pts (42%)

Mikkelsen et al. Chest, 2010

Mikkelsen et al. Chest, 2010

4 Risk Factors Associated with Non-

adherence

• Female patient (p=0.001)

• Female physician (p=0.041)

• Lactate as qualifying criterion (p=0.018)

• Skin infections or urinary tract infections

• Non-consultation of severe sepsis

service (p<0.001)

Mikkelsen et al. Chest, 2010

Protocolized Care

• 2013, protocolized care = standard of care

• Objective interventions/Objective endpoints

• Goal: differentiate Responders from Non-Responders @ each stage of resuscitation

• Potential Organ Dysfunction Immediate attention regardless of patient location in health care system

• EGDT most famous type of protocolized care

• New insights arrive…

The ProCESS Trial

• Three arms:

1.Protocol-based EGDT

2.Protocol-based standard therapy Similar to # 1 but no mandated CVC, transfusion only

for Hgb<7.5, fluids only to “volume repleted”, no specific pressor mandates

3.“Usual care” (clinician’s preference)

ProCESS

• 51 ICUs in Australia and New Zealand

• 1600 patients presenting to the ED in early

septic shock

• 2 SIRS, source of infection, hypotension or

hypoperfusion

• Antibiotics prior to randomization

• Randomized to EGDT vs. usual care

ARISE Investigators. NEJM, 2015

ARISE

ARISE Investigators. NEJM, 2015

ProMISe

Mouncey et al. NEJM, 2015

Preventing Readmissions

Post-Discharge Problems

• “Unfortunately, discharge from a severe

sepsis hospitalization is all too often the

beginning of the end”

• Iwashnya and colleagues:

– the 3-year case-fatality rate remains

stubbornly above 70%

– Readmissions common

– Costs are staggering

Buchmann, “You Tell Me.” CCM, 2015

Readmissions @ Penn

• Patients admitted with septic shock (serum

lactate ≥ 4 mmol/L or refractory hypotension)

and discharged alive to a non- hospice

setting between 2007 and 2010

• 269 at-risk survivors:

– 63 (23.4%; 95% CI, 18.2–28.5) were readmitted

within 30 days of discharge

– 12 (4.5%; 95% CI, 2.3–7.7) returned to the ED for

a treat-and-release visit

Ortego et al. CCM, 2015

Readmissions @ Penn

• 75% of readmissions occurred within

15 days of discharge:

– more likely in oncology pts (p = 0.001)

– pts with a longer hospital LOS (p = 0.04)

– 16% resulted in death or d/c to hospice

– Potentially related to the index septic shock

hospitalization in 78% (49/63) of cases

– 46% of readmissions were infection-related

Ortego et al. CCM, 2015

Case Conclusion

• Evaluated by ESS

• Went to IR for a percutaneous drain

• E. coli in blood cultures and drainage fluid

• On NE and DOBUT for 3 days

• Clinically stabilized

• Delayed cholecystectomy

• Discharged in good condition on HD-17

Conclusions-1

• Osler was right—the patient dies as much from the body’s response to infection as from the infection itself

• Huge epidemiologic burden of sepsis

• Recognition: major hurdle

• SIRS: Helpful but not infallible

• Lactate: marker for critical illness and powerful screening tool

Conclusions-2

• Protocolized care improves outcomes

• Modify to fit different resource settings

• Antibiotics: – integrate into early resuscitation strategies

– prioritize along w/ other aspects of initial critical care

• Rivers’ fundamental insight: – moving aggressive, protocolized care to the most

proximate phase of critical illness

• The optimal details remain to be elucidated

• SEP-1 adherence should further improve care