Sepsis as a Medical Emergency

Global Sepsis AllianceJim O’Brien, MD, MScProfessor Assistant Director, Medical Intensive Care Unit The Ohio State University Medical Center Sepsis Alliance, Board of Directors

Disclosures, 2004-present

•University grant monies: • Davis/Bremer Medical Research Award ($50K, 3/05 – 2/07)

•Non-industry grant monies: • NHLBI K23 HL075076 ($520,992, 4/05 – 3/09); • NIH Clinical Research Loan Repayment Program ($152,781, 10/03-6/05, 7/06-6/10 )

•Industry grant monies: • PI for aerosolized amikacin (Aerogen, $0, 8/05 – 6/06)• PI for calfactant (Pneuma, $0, 9/08 – current)

•Consultant/Speakers’ Bureau: • Gave lecture on future perspectives on sepsis definitions. Honorarium from Brahms

donated to Sepsis Alliance. I received airfare and two night’s hotel accommodations totaling approximately $1500 in value (2009).

• Unrestricted educational grant from Lilly to present talk at SCCM (2005)• Consultant to Medical Simulation Corporation ($4000, 2005-2006)• Co-author on manuscript with Lilly employees• Consultant to Keimar, Inc ($0)• Board of Directors, Sepsis Alliance

I think sepsis is under-appreciated.

I think sepsis is under-funded.

I think we over-complicate sepsis care (MD effect)

I think that I have less to offer septic patients once they are in the ICU.

I think that it is inevitable that we will get our act together. Only question is how many of us will die first.

•What is sepsis?

•How common is sepsis?

•What causes sepsis?

•How do you treat sepsis?

•84yo Caucasian male with h/o Parkinson’s and remote history of gun shot wound

•Presents to the ED from his residence with altered mental status, fever and smelly urine

•Temp 102.3 P 118 R 32 BP 78/34 •84% SPO2

Karol Wojtyla (1920-2005)

Pre and post-discharge

Hospitalization

24 hours

6 hours

Recognition

Resuscitation

Initial Management

Maintenance

Recovery

Sepsis Recognition in OSUMC ED

Patients admitted through ED Main Jan-March 2009

(n = 4951)

Patients with sepsis upon ED presentation

(n = 137, 27.4%)

Recognized as septic inED notes and/or H&P

(n = 35, 25.5%)

Not recognized as septic in ED notes and/or H&P

(n = 102, 74.4%)

Randomly selected charts reviewed

(n = 500, 53.1%)

Received ATBs within 24 hrs of admission

(n = 941, 19.0%)

Dreher et al Manuscript in preparation

That extrapolates to 768 unrecognized septic patients/year at

OSU Main ED alone!

That extrapolates to 768 unrecognized septic patients/year at

OSU Main ED alone!

So what is sepsis anyway?

According to the Consensus definition, what is sepsis?

1. Blood poisoning

2. Bacteremia

3. Shock due to infection

4. Fever due to infection

5. None of the above

Sepsis: Defining a Disease Continuum

SIRS = Systemic Inflammatory Response Syndrome

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma

Severe SepsisSevere Sepsis

, et al. Chest 1992;101:1644, Opal SM, et al. Crit Care Med 2000;28:S81

SIRS with a presumed orconfirmed infectious

process

According to the Consensus Conference definition, which of the following is NOT a SIRS criterion?

1. SBP<90 and/or MAP <70

2. Heart rate >90

3. Respiratory rate >20 or PaCO2<32

4. Temperature >38⁰C or <36⁰C

5. WBC >12K or <4K or >10% bands

Sepsis: Defining a Disease Continuum

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% immature

neutrophils

SIRS = Systemic Inflammatory Response Syndrome

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma

Severe SepsisSevere Sepsis

Adapted from: Bone RC, et al. Chest 1992;101:1644 Opal SM, et al. Crit Care Med 2000;28:S81

•84yo Caucasian male with h/o Parkinson’s and remote history of gun shot wound

•Presents to the ED from his residence with altered mental status, fever and smelly urine

•Temp 102.3 P 118 R 32 BP 78/34 •84% SPO2

Does he have sepsis?

Is he sick or not sick?

• Sepsis with 1 sign of organ failure• Cardiovascular (refractory

hypotension)• Renal• Respiratory• Hepatic• Hematologic• CNS• Metabolic acidosis

Sepsis: Defining a Disease Continuum

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma

Severe SepsisSevere Sepsis

Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207

TachycardiaHypotensionAltered CVP

Altered PAOP

OliguriaAnuria

Creatinine

Platelets PT/APTT Protein C D-dimer

Jaundice Enzymes Albumin

PT

Altered Consciousness

ConfusionPsychosis

TachypneaPaO2 <70 mm Hg

SaO2 <90%

PaO2/FiO2 300

Neurologic

Respiratory

Hepatic

Renal

Coagulation

Cardiovascular

Mortality increases with increasing organ failure

Hebert et al. Chest 1993;104:230-5

How sick is he?

•WBC 30K with 20% bands

•Shock

•ABG 7.20/28/42/15 on 100% FiO2

•Platelets normal, INR 1.7

•LFTs normal

•BUN 32, Creatinine 1.9

•Delirious

This seems kind of bad.Glad it doesn’t happen much

RECOGNITION

Sepsis incidence, 1999-2003

Sepsis Severe Sepsis Septic shock Death in sepsis

Inci

dence

X10

3

22%22%

44%44%

73%73%

O’Brien et al. Under review

Sepsis incidence, 1999-2003

Sepsis Severe Sepsis Septic shock Death in sepsis

Inci

dence

X10

3

O’Brien et al. Under review

In 2003,

1 in 35 of ALL hospital admissions involved sepsis

1 in 66 involved severe sepsis

1 in 233 involved septic shock

Sepsis incidence, 1999-2003

Sepsis Severe Sepsis Septic shock Death in sepsis

Inci

dence

X10

3

O’Brien et al. Under review

20.7%21.7% 16%

16%

Sepsis incidence, 1999-2003

Sepsis Severe Sepsis Septic shock Death in sepsis

Inci

dence

X10

3

O’Brien et al. Under review

20.7%21.7% 16%

16%

In 2003,

1 in 35 of ALL hospital admissions involved sepsis

1 in 66 involved severe sepsis

1 in 233 involved septic shock

22%22%

44%44%

73%73%

16%16%

In 2003, 23.2% of all deaths during hospitalization involved sepsis

(up from 19.4% in 1999)

In other words…. 1 in 4.3 deaths of hospitalized patients

involves sepsis

215,000 deaths a year in US

228 Deathsevery ~9 h

2974 Deaths Every ~5 days

Deaths fromBreast cancerLung Cancer

+ Prostate CancerTOTAL < Deaths from Sepsis

Deaths fromBreast cancerLung Cancer

+ Prostate CancerTOTAL < Deaths from Sepsis

Severe Sepsis Costs a Lot

Angus et al, Crit Care Med 2001; 29: 1303-10

•Average LOS 19.6 days•Average cost $22,100/case•Total national hospital cost was $16.7 BILLION•52.3% of costs in those >64 years•30.8% total costs in those >74 years

Age

Average per-patient cost

Total national cost

This doesn’t sound that greatMaybe we should figure out what causes this

Risk factors and Pathogenesis

The Pathogenesis of Sepsis

Response to Stimulus

•Inflammation•Immunosuppression

•Coagulopathy•Mitochondrial dysfunction

Infectious Agents

•Endotoxin/LPS•Lipopeptides•Lipoteichoic acid•DNA•Flagellin

Susceptible Host

•Co-morbidities•Age•Genetic polymorphisms

SEPSIS

Organisms Found in Sepsis

Only about 30% have a positive blood culture

Martin et al, NEJM 2003:348;1546-54.

Sites of Infection in Severe Sepsis

Angus et al, Crit Care Med 2001; 29: 1303-10

Association of Clinical Risk Factors with Sepsis and Severe Sepsis

Adapted from O’Brien et al. Am J Med 2007.

TREATMENT

All right, all right, I get it.

But isn’t that guy dying on us?

Shouldn’t we do something about that?

Pre and post-discharge

Hospitalization

24 hours

6 hours

Suspicion

Resuscitation

Initial Management

Maintenance

Recovery

Which of these is sepsis?

1. Confusion, cough, nausea

2. Fever, shortness of breath, chest pain

3. Abdominal pain, lightheadedness, diarrhea

4. Rash, leg swelling, anorexia

5. Tachycardia, chills, sweating

We have to ACT when we are uncertain.

We have to ACT when we are uncertain.

Pre and post-discharge

Hospitalization

24 hours

6 hours

Recognition

Resuscitation

Initial Management

Maintenance

Recovery

Suspicion

Antibiotic Therapy & Blood Cultures

All subjects Recognized

Not recognized

P value

Hours to Order 1.9 (1.1 – 3.0)

1.3 (1.0 – 2.0)

2.1 (1.3 – 3.5)

0.012

Hours to Administration

2.6 (1.9 – 3.9)

2.1 (1.7 – 3.7)

2.8 (2.0 – 4.5)

0.043

p = 0.004 p = 0.165 p = 0.001

All Subjects: 56.2% 30.7% 77.4%

Dre

her

et

al M

an

usc

rip

t in

pre

para

tion

…

RESUSCITATION PHASEGOAL: Keep him alive for 24 hours

•A – Airway• Intubation

•B – Breathing• Mechanical ventilation

•C – Circulation• IV access• IV volume• Vasopressors• Goal directed therapy

Treat theInfection

Antibiotics – Go BIG early

• Every hour in delay of appropriate atbx = 7.6% lower survival

• Median time to appropriate atbx = 6h

Get cxs before atbx if WON’T DELAY ATBXBegin IV atbx ASAP and ALWAYS within 1h

Use broad-spectrum atbx with activity against bugs and sites

Kumar et al. Crit Care Med 2006; 34: 1589-96.

The first 12 hours matters even more

Funk and Kumar, Crit Care Clinics 2011; 53-76.

For first 12 hours, 1% mortality per 5 minute delay

For first 12 hours, 1% mortality per 5 minute delay

Shock to effective antibiotic time and mortality in septic shock*

Adapted from Kumar et al. Crit Care Med 2006; 34: 1589-96.

*Assuming 130,000 septic shock cases per year

By getting shock-to-antibiotic times of <2h for ALL septic shock

patients,we would save

32,360 lives per year.(89 people a day)

Septic Shock in OSUMC MICUs

Pre-intervention During Intervention Post Intervention

8/24/08 – 12/31/08 1/1/09 – 3/31/09 4/1/09 – 6/7/10

N 121 82 281

Time to atbx in hrs, median (IQR)

5.4 (1.7 – 11.5)

1.7 (0.2 – 3.8)

2.0 (1.0 – 5.2)

Atbx within 2 hours 29.8% 56.1% 50.5%

Patients with sepsis onset within 24h of ICU admissionSOFA shock score of >0

Septic Shock in OSUMC MICUsPre-

interventionDuring

InterventionPost

Intervention

8/24/08 – 12/31/08

1/1/09 – 3/31/09

4/1/09 – 6/7/10

Hospital mortality 36 (26.4%) 21 (25.6%) 56 (19.9%)

Observed/Expected Mortality Ratio (SAPS II)

0.41 0.35 0.30

Expected deaths if O/E as in Pre-intervention period

24.8 77.0

Lives saved 3.8 (in 3 months)

21.0(in 14 months)

Patients with sepsis onset within 24h of ICU admissionSOFA shock score of >0

Addressing circulation in sepsis

•Why is circulation affected in sepsis?• Dehydration

• Loss of vascular tone

• Loss of endothelial integrity

• Shunting

• Occlusion

• Decreased cardiac output

•How is circulation addressed in sepsis?• Replete intravascular

volume

• Vasopressors

• Interventions directed at oxygen delivery:extraction balance

HEART

ARTERIESVEINS

ORGANS

O2

O2

O2

O2

O2

O2

O2

O2

HEART

ARTERIESVEINS

ORGANS

O2

O2

O2

O2

O2

O2

O2

O2

STEP 1: Make sure the pump is full

(volume depletion)

The C in the ABCs:Volume Resuscitation

Assess for Volume Depletion•History

•Exam - Organ perfusion – skin, brain, kidneys•Measure intravascular pressures – arterial, central venous

Assess for Volume Depletion•History

•Exam - Organ perfusion – skin, brain, kidneys•Measure intravascular pressures – arterial, central venous

Administer a “Fluid Challenge”•1000mL crystalloid OR 500mL colloid

•Intravenous over 30 minutes

See what happens•Blood pressure (mean arterial pressure

>65)•Central venous pressure 8-12•Urine output 0.5 ml/kg/h

•Heart rate

See what happens•Blood pressure (mean arterial pressure

>65)•Central venous pressure 8-12•Urine output 0.5 ml/kg/h

•Heart rate

A Comparison of Albumin and Saline for FluidResuscitation in the Intensive Care Unit

NEJM 2004; 350: 2247-56

•N=6997

•Randomized to NS or 4% albumin for any resuscitation

•In patients with severe sepsis:

• 30.7% mortality with albumin

• 35.3% mortality with NS

HEART

ARTERIESVEINS

ORGANS

O2

O2

O2

O2

O2

O2

O2

O2

STEP 2: Make the train is on a fast track (vascular

tone)

STEP 1: Make sure the pump is full

(volume depletion)

The C in the ABCs:Vasopressors In Septic Shock

Heart Rate Contractility Vasoconstriction

Dopamine

Low dose 0 0 1-

Medium dose 2+ 2+ 0

High dose 2+ 2+ 3+

Dobutamine 1+ 4+ 1-

Norepinephrine 2+ 2+ 4+

Phenylephrine 2- 0 4+

Epinephrine 4+ 4+ 4+

Vasopressin* 0 1- 3+

HEART

ARTERIESVEINS

ORGANS

O2

O2

O2

O2

O2

O2

O2

O2

STEP 2: Make the train is on a fast track (vascular

tone)

STEP 1: Make sure the pump is full

(volume depletion)

STEP 3: See if supply is keeping up with demand

Step 3: Is oxygen supply keeping up with demand?

Central venous O2 saturation

Reflects oxygen extractionby tissue, relative to

oxygen delivery

Lactate clearanceReflects transitionfrom anaerobic to

aerobic metabolism

Oxygen delivery is determined by:Hemoglobin

Cardiac output Arterial oxygen saturation

Interventions to address oxygen delivery/consumption balance

Optimize venous filling pressures, arterial blood pressure

Optimize venous filling pressures, arterial blood pressure

Imbalance between O2 delivery: extraction-CVO2<70%

-Lactate clearance <10%

Imbalance between O2 delivery: extraction-CVO2<70%

-Lactate clearance <10%

Hgb <10?Hgb <10?

DobutamineDobutamine

TransfuseTransfuse

Increase COIncrease CO

YES

YESNO

EGDT – “Rivers” resulted in different care

Control EGDT p

Crystalloid, mean, L

0-<6h 3.5 5.0 <0.0001

6-72h 10.6 8.6 0.01

Vasopressors

0-<6h 30.3% 27.4% 0.62

6-72h 42.9% 29.1% 0.03

Dobutamine

0-<6h 0.8% 13.7% <0.0001

6-72h 8.4% 14.5% 0.14

PRCs

0-<6h 18.5% 64.1% <0.0001

6-72h 32.8% 11.1% <0.0001

N Engl J Med 2001;345:1368

Control EGDT P

Hospital mortality

46.5% 30.5% 0.009

28d mortality 49.2% 33.3% 0.01

60d mortality 56.9% 44.3% 0.03

EGDT – “Rivers” resulted in different care

Control EGDT p

Crystalloid, mean, L

0-<6h 3.5 5.0 <0.0001

6-72h 10.6 8.6 0.01

Vasopressors

0-<6h 30.3% 27.4% 0.62

6-72h 42.9% 29.1% 0.03

Dobutamine

0-<6h 0.8% 13.7% <0.0001

6-72h 8.4% 14.5% 0.14

PRCs

0-<6h 18.5% 64.1% <0.0001

6-72h 32.8% 11.1% <0.0001

N Engl J Med 2001;345:1368

Control EGDT P

Hospital mortality

46.5% 30.5% 0.009

28d mortality 49.2% 33.3% 0.01

60d mortality 56.9% 44.3% 0.03

An approach using lactate clearance (vs EGDT/CVO2) resulted in nearly identical care and

similar outcomes.

Hospital mortalityLactate clearance = 17%

EGDT/CVO2 = 23%

JAMA 2010;303:739-46

An approach using lactate clearance (vs EGDT/CVO2) resulted in nearly identical care and

similar outcomes.

Hospital mortalityLactate clearance = 17%

EGDT/CVO2 = 23%

JAMA 2010;303:739-46

•Patient is given piperacillin/tazobactam, amikacin and vancomycin

•Central venous catheter placed, CVP=3•Given fluid challenge and requires norepinephrine•Ultimately receives 8L of normal saline in first 4h of presentation, CVP 12

•Intubated for respiratory failure

•CXR shows bilateralinfiltrates

Pre and post-discharge

Hospitalization

24 hours

6 hours

Recognition

Resuscitation

Initial Management

Maintenance

Recovery

INITIAL MANAGEMENT PHASEGOAL: Let’s get him better

•Supportive care

• Identify organ failures

• Customize antibiotics based on cultures/sensitivities

• Additional diagnostic testing

• Goals of care discussions

•Specific care

• Drotrecogin alfa (activated) [Xigris®]

• Lung protective ventilation

• Conservative fluid management

APC Links Coagulation & Inflammation

N Engl J Med 2001;344:699-709.

Drotrecogin Alfa (Activated) Significantly Reduced Mortality in PROWESS

Bernard GR, et al. N Engl J Med 2001;344:699-709.

00 77 1414 2121 2828

7070

8080

9090

100100

Days from Start of Infusion to DeathDays from Start of Infusion to Death

Perc

ent S

urvi

vors

Perc

ent S

urvi

vors

P=.006 (stratified log-rank test)00

Placebo(n=840)

Drotrecogin alfa (activated) (n=850)

6% Absolute 6% Absolute mortality mortality differencedifference

NNT = 17NNT = 17

Patient selection is important

•“High risk” of dying

•APACHE II score >24 NNT = 8

•Multi-organ failure NNT=14

•Respiratory failure NNT=17

•Shock NNT=15

•40% probability of dying?

•“Low risk” of bleeding

•serious bleeding: 2 to 5%

•ICH: 0.2 to 0.5%

•Bleeding associated with: Instrumentation Trauma Thrombocytopenia (<30) Meningitis INR >3

Acute Lung Injury and the Acute Respiratory Distress Syndrome … see prior talk

•Started on drotrecogin alfa (activated) for septic shock with high risk of death

•Tidal volumes reduced to 6 ml/kg PBW•Placed on continuous renal replacement therapy for

sepsis-associated renal failure•Blood and urine cultures grow E. coli – antibiotics changed

to imipenem based on antibiotic sensitivities•Shock resolves over 4d•10kg heavier than admit weight

Pre and post-discharge

Hospitalization

24 hours

6 hours

Recognition

Resuscitation

Initial Management

Maintenance

Recovery

MAINTENANCE PHASEGOAL: Don’t kill him

•Avoid nosocomial complications

• Ventilator-induced lung injury

• Get tubes and lines out of him

• Clots and bleeding

•Avoid new infection

• Hand washing

• Semi-recumbent position

• Get tubes and lines out of him

•Minimize transfusions

•Maintained on continuous infusions of benzodiazepines and opioids for “papal comfort”

•Oxygenation improves but doesn’t wake up after sedative stopped

•CT head negative•Gets 2u packed red cells for Hgb 8.0•Develops hospital-associated pneumonia and catheter-related

blood stream infection•Discharged to long-term acute care hospital with tracheostomy

tube and percutaneous feeding tube after 28 days in ICU

Pre and post-discharge

Hospitalization

24 hours

6 hours

Recognition

Resuscitation

Initial Management

Maintenance

Recovery

Long-term Cognitive Impairment and Functional Disability Among Survivors of Severe Sepsis

•Compared 516 severe sepsis survivors with 4517 survivors of non-sepsis hospitalization

•Prevalence of mod/severe cognitive impairment increased by 10.6% after sepsis AdjOR 3.34 (95% CI 1.53 – 7.25)

•Severe sepsis associated with development of 1.5 new limitations in ADLs More rapid rate of developing further limitations

•59% of sepsis survivors had worsened cognitive and/or physical function

•Significantly worse than for non-sepsis hospitalizations

Iwashyna et al. JAMA 2010;304(16):1787-94

What is it?

•SIRS + Infection = Sepsis

•Sepsis + Organ Failure = Severe Sepsis

•Sepsis + Shock = Septic Shock

•Mortality increases with more organ failure

How common is it?

•Significant mortality – Top 10 cause of death

•Significant morbidity

•Significant cost

•Is getting more common

What causes it?

•Inflammation

•Coagulopathy

•Blood flow

•Cell failure

•Organ failure

•Death

•Host factors

•Infection factors

•Nosocomial complications VAP/BSI Ventilators

How do you treat it?•Recognition

•Resuscitation = ABCs + Atbx Goal-directed therapy

•Initial Management Customize care Drotrecogin alfa (activated)

•Maintenance Avoid complications• Transfusion• Sedation• Ventilation

You can save lives

•Say Sepsis

•Suspect Sepsis

•Simplify Sepsis Treat it like a medical emergency

Antibiotics Fluids

www.sepsisalliance.org