Eleana M. Zamora, MDAssistant Professor of MedicineDivision of Pulmonary, Critical Care, and Sleep

Be able to define SIRS, sepsis, severe sepsis, and septic shockDescribe the epidemiology of sepsisDescribe patients who are at risk for sepsisList the main treatment goals for septic shock

*Sands KE et al. JAMA. 1997;278:234‐40; §Murphy SL. National Vital Statistics Reports. 

‡Angus DC et al. Crit Care Med. 2001;29:S109. 

Major cause of morbidity and mortality worldwide• Leading cause of death in noncoronary ICUs (US)*• 11th leading cause of death overall (US) †§

More than 750,000 cases of severe sepsis in US annually‡

In the US, more than 500 patients die of severe sepsis daily‡

Sepsis accounts for 40% ICU expendituresSepsis cases increasing @ 1.5% yearly

Used with permission, S.Simpson, MD, KU, 2008

Body’s response to infection

Is a medical emergencySepsis causes interruption of normal blood flow and oxygenation to organs

UNM: about 35% of all deaths on Medicine service coded for sepsis or infection as primary cause of death

Condition Prevalence Deaths Mortality

AMI (1) 900,000 225,000 25%Stroke (2) 700,000 163,500 23%Trauma (3)

(Motor Vehicle)2.9 million 42,643 1.5%

Severe Sepsis (4)

751,000 215,000 29%

Source: (1) Ryan TJ, et al. ACC/AHA Guidelines for management of patients with AMI. JACC. 1996; 28: 1328-1428. (2) American Heart Association. Heart Disease and Stroke Statistics –2005 Update. Available at: www.americanheart.org. (3) National Highway Traffic Safety Administration. Traffic Safety Facts 2003: A Compilation of Motor Vehicle Crash Data from the Fatality Analysis Reporting System and the General Estimates System. Available at http://www.nhtsa.dot.gov/. (4) Angus DC et al. Crit Care Med 2001;29(7): 1303-1310.

Angus DC, et al. Crit Care Med. 2001.

Age (y)

<1 1-4

5-9

10-1

415

-19

20-2

425

-29

30-3

435

-39

40-4

445

-49

50-5

455

-59

60-6

465

-69

70-7

475

-79

80-8

4 85

Inci

denc

e (p

er 1

000

pop)

0

5

10

15

20

25

30Cases Incidence

0

20,000

40,000

60,000

80,000

100,000

120,000

No.

of C

ases

>

Sepsis: A Deadly Continuum

A clinical response arising from a nonspecific insult, with ≥2 of the following:• T >38oC or <36oC• HR >90 beats/min• RR >20/min• WBC >12,000/mm3 or <4,000/mm3 or >10% bands

SIRS with apresumedor confirmed infectiousprocess

Chest 1992;101:1644.

SepsisSIRSSevere Sepsis

SepticShock

Sepsis with organ 

dysfunction

RefractoryHypotensionRelated toSepsis

Widespread inflammatory response to a variety of severe clinical insults

Clinically recognized by the presence of 2 or more of the following:

Temperature >38 C or < 36 CHeart Rate >90Respiratory Rate > 20 or PaCO2 <32WBC > 12,000, < 4000 or > 10% immature forms

SIRS criteria + evidence of infection

White cells in normally sterile body fluidPerforated viscusRadiographic evidence of pneumoniaSyndrome associated with a high risk of infection (HIV, neutropenia, etc)

Sepsis + evidence of organ dysfunction:

CV: mottled skin, left heart failureNeuro: Change in mental statusRenal: Urine output < 0.5 ml/kg body weight/hr for 1 hour despite volume resuscitationPulmonary: PaO2/FiO2 < 250 if other organ dysfunction present or < 200 if the lung is the only dysfunctional organHematologic: DIC, Platelet count < 80K or decreased by 50% in 3 daysMetabolic: pH < 7.3 and plasma lactate > 1.5 x upper normal

Severe sepsis + hypotension  

MAP < 60 despite adequate fluid resuscitationUse of pressors

Adapted from: Bone RC et al. Chest. 1992;101:1644‐55.Used with permission, S.Simpson, MD, KU, 2008

SevereSepsis

Trauma

Infection

Sepsis Other

Pancreatitis

Burns

SIRS

Prospectively enrolled 2527 patients who met SIRS criteriaFollowed for 28 days or discharge for development of any stage of the sepsis continuum

Incidence (No. pts, (%)) Mortality (%)

No progression 1301 (52%) 7%

Sepsis 649 (26%) 16%

Severe Sepsis 467 (18%) 20%

Septic Shock 110 (4%) 46%

Rangel‐Frausto MS, et.al. JAMA 273:117‐23, 1995

Severe Sepsis:  Mortality 20‐35%

Septic shock:  Mortality 40‐60%

Global Tissue Hypoxia

Increased MetabolicDemands

Hypovolemia VasodilationMyocardial Depression

Microvascular AlterationsO2 DeliveryO2 Demand

After Fink. Crit Care Clin 2002.Used with permission, S.Simpson, MD, KU, 2008

NormalLow arterial pressure causes systemic vascular smooth muscle vasconstriction (high SVR)Examples: cardiogenic shock, hemorrhagic shock

SepsisCytokines, NO, etc cause peripheral vasodilation(low SVR)Low BP (hypotension) and low SVR

TachycardiaHypotension

OliguriaAnuria

↑ Creatinine

↓ Platelets↑ PT/APTT↓ Protein C↑ D-dimer

Altered Consciousness

ConfusionPsychosis

TachypneaPaO2 <70 mm Hg

SaO2 <90%PaO2/FiO2 ≤300

Jaundice↑ Enzymes↓ Albumin

↑ PT

Lactic acidosis

Used with permission, S.Simpson, MD, KU, 2008

CirculationHypotension, increases in microvascular permeability

LungPulmonary Edema, hypoxemia

GI tractTranslocation of bacteria, Liver Failure

Nervous SystemEncephalopathy, Critical Illness Polyneuropathy

KidneyAcute Tubular Necrosis, renal failure

Patients with positive blood cultures (septicemia, bacteremia)

Comorbidities causing host‐defense depression: AIDS, renal or liver failure, neoplasms, chronic immunosuppression, diabetes

Middle‐aged, elderly

Very young, very oldWeakened immune systemWound or injuries (burns, car accidents)Alcohol or other drug abuseIndwelling devices

Central lines, foley catheters, wound vacsGenetic factorsHospital factors

Nosocomial infections, antibiotic resistance

AntibioticsIV Fluids Vasoactive agents (pressors)Source control

Steroid therapy ? (adrenal insufficiency)Ventilatory strategiesGlycemic controlPrevention of secondary infections

Early aggressive fluid resuscitationAntibiotics earlyBP support (Dopamine, vasopressin, norepinephrine)? Hydrocortisone for adrenal insufficiencyGlycemic control (blood sugars)

6 Hour Sepsis Bundle1. Measure serum lactate2. Blood cultures prior to Abx3. Broad spectrum Abx (3hrs)4. If hypotensive or lactate>4

Fluid bolusVasopressors for MAP> 65

5. If persistent BP<65 or Lactate >4

Achieve CVP>8SVO2 >65

24 Hour Bundle1. ? Steroids as needed2. APC if indicated (no 

longer recommended)3. Tight glycemic control4. ARDSnet ventilator 

protocol

EGDT: Early Goal Directed Therapy

Use is evidence‐based:• Combine multiple elements known to be effective

• Outcome is additive or synergistic• Framework that leverages change• Avoids a piecemeal approach

Gao, et al. Critical Care 2005, 9:R764‐R770.With Permission from S. Simpson, MD,, Kansas University, 2008

The Importance of Early Goal-DirectedTherapy for Sepsis Induced Hypoperfusion

Adapted from Table 3, page 1374, with permission from Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med2001; 345:1368-1377

In-hospital mortality

(all patients)

0

10

20

30

40

50

60 Standard therapyEGDT

28-day mortality

60-day mortality

NNT to prevent 1 event (death) = 6-8M

orta

lity

(%)

3 pathways

Green (sepsis)

Yellow (severe sepsis, lactate 2-4)

Red (severe sepsis or septic shock)

Address cause: Treat infection

Intravascular volume resuscitation

Cardiovascular support

Support of dysfunctional organ systems

The Importance of Early Goal‐DirectedTherapy for Sepsis Induced Hypoperfusion 

Adapted from Table 3, page 1374, from Rivers E, Nguyen B, Havstad S, et al. Early goal‐directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368‐1377

In-hospital mortality

(all patients)

0

10

20

30

40

50

60 Standard therapyEGDT

28-day mortality

60-day mortality

NNT to prevent 1 event (death) = 6-8M

orta

lity

(%)

Abx within 1 hr hypotension:  79.9% survivalSurvival decreased 7.6% with each hour of delayMortality increased by 2nd hour post hypotension Time to initiation of antibiotics was the single strongest predictor of outcome

Inappropriate antibiotic therapy is bad

20% of patients receive inappropriate therapySurvival of those with appropriate therapy 52%Survival of inappropriate therapy 10%

Adequate fluid resuscitation (quickly)How to gauge?

CVPFluid responsivenessCVPSVVPassive leg raiseLactate levels

EGDT is designed to: 

Recognize patients with severe sepsis as early as possible and begin treatment quickly

Assess laboratory and hemodynamic variables for acute organ dysfunction

Delineate time targets for delivery of treatment of patients with sepsis

Develop hospital‐specific bundled protocols

Earlier treatment leads to better outcomes

EGDT is designed to: 

Recognize patients with severe sepsis as early as possible and begin treatment quickly

Assess laboratory and hemodynamic variables for acute organ dysfunction

Delineate time targets for delivery of treatment of patients with sepsis

Develop hospital‐specific bundled protocols

Earlier treatment leads to better outcomes

• Mortality improvement 

• Bundled protocols improve outcomes• But not all individual bundle elements have been 

shown to specifically improve mortality• Early and appropriate antibiotics

• Aggressive fluid resuscitation improve outcomes

ezamora@salud.unm.edu