Septic Shock: Diagnosis and

Management

Society of Critical Care Medicine ©2014

Overview
•Definitions
•Epidemiology
– Incidence of sepsis
– Predisposing factors for sepsis
– Risk factors for mortality due to sepsis
•Pathophysiology
•Management
•Summary
Society of Critical Care Medicine ©2014 2
Definitions
1991 SCCM/ACCP Consensus Conference
•Systemic inflammatory response syndrome (SIRS) = > 2
of the following: temp > 38.3°C or < 36°C,
HR > 90/min, RR > 20/min, WBC > 12,000 or
< 4,000/mm3 or > 10% bands
•Sepsis = SIRS + presumed or proven infection
•Severe sepsis = Sepsis + organ dysfunction
•Septic shock = Sepsis + hypotension despite
“adequate” fluid resuscitation
Crit Care Med. 1992;20:864-874.

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2001 Conference Diagnostic Criteria for Sepsis
• Infection PLUS Some of the Following:
– Fever – Thrombocytopenia
– Arterial hypotension – Decreased capillary refill or
– Increased CRP mottling
– Increased PCT – Leukocytosis
– Increased SvO2 – Leukopenia
– Increased cardiac output – Hypothermia
– Tachycardia – Ileus
– Arterial hypoxemia – Altered mental status
– Acute oliguria – Significant edema or positive
– Increased creatinine fluid balance
– Coagulation abnormalities – Hyperbilirubinemia
– Hyperlactatemia – Hyperglycemia
Levy MM et al. Intensive Care Med. 2003.
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2001 Conference
Diagnostic Criteria for Sepsis
• • Infection
NeitherPLUS
a symptom norFollowing
Some of the any laboratory
: parameter
– Fever – Hyperlactatemia
alone is specific
– Arterial hypotension
to sepsis itself
– Thrombocytopenia
• –Groups
Increasedof symptoms and laboratory
CRP – Decreasedparameters
capillary refill or
– Increased PCT mottling
could be used
– Increased SvO2
in combination – Leukocytosis
• –Sepsis criteria
Increased need to be established
cardiac output – Leukopeniafor research
–and – Hypothermia
clinical purposes
Tachycardia
– Ileus
– Arterial hypoxemia
• –Early
Acutedetection
oliguria of sepsis is critical
– Altered tomental
initiation
status of
–appropriate – Significant edema or positive
therapy
Increased creatinine
– Coagulation abnormalities fluid balance
– Hyperbilirubinemia
– Hyperglycemia
Levy MM et al. Intensive Care Med. 2003.
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2001 Conference Severe Sepsis and Septic Shock
Definitions
•Definition of severe sepsis remained unchanged
– Severe sepsis is sepsis with organ dysfunction
– Organ dysfunction defined by SOFA criteria
•Characteristics of septic shock
– Mean arterial pressure <65 mm Hg
– Systolic pressure <90 mm Hg
– Systolic pressure decrease >40 mm Hg from baseline
– Despite adequate fluid resuscitation
– In the absence of other causes of hypotension
Levy MM et al. Intensive Care Med. 2003;31:1250-56.
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Acute Organ Dysfunction as a Marker of Severe Sepsis
Altered Tachycardia
Consciousness Hypotension
Confusion Altered CVP
Psychosis Altered PAOP

Tachypnea
PaO2 <70 mm Hg
Oliguria
SaO2 <90%
Anuria
PaO2/FiO2 300
 Creatinine
 Lactate

Jaundice
 Platelets
 Enzymes
 PT/APTT
 Albumin
 Protein C
 PT
 D-dimer
Balk RA. Crit Care Clin. 2000;16:337-52.
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Sequential Organ Failure Assessment (SOFA)
Score

Vincent JL et al. Intensive Care Med. 1996.

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Overview
•Definitions
•Epidemiology
– Incidence of sepsis
– Predisposing factors for sepsis
– Risk factors for mortality due to sepsis
•Pathophysiology
•Summary

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Classic Papers

Angus DC et al. Crit Care Med. 2001;29:1303-1310.

Martin GS et al. N Engl J Med. 2003;348:1546-1554.

Society of Critical Care Medicine ©2014 10

Severe Sepsis and Septic Shock:
Epidemiology
•~750,000 cases annually in the US
•~19 million cases annually worldwide
•10-15% of ICU admissions
•Most common cause of death in noncoronary
ICUs
•25-30% mortality rate in RCTs
•Costs: $12.3 billion in 2007
Angus DC, et al. Crit Care Med 2001;29:1303-10; Padkin A, et al. Crit Care Med 2003;31:2332-38.
Wier LM, et al. AHRQ Statistical Brief 2010; Kumar G, et al. Chest 2011;140:1232-31.

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Trends in Severe Sepsis

Dombrovskiy VY et al. Crit Care Med. 2007.

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Severe Sepsis and Septic Shock: Risk Factors for
Incidence and Mortality
•Age: higher in infants and elderly
•Higher in males than females
•Higher in Blacks than Whites
•Higher with chronic diseases (e.g., COPD,
cancer, AIDS)
•Immunosuppressive agents
•Genetic factors
Angus DC, et al. Crit Care Med 2001;29:1303-10.
Mayr FB, et al. JAMA 2010;303:2495-503.

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Genetic Variation and Sepsis
• Some Association Studies
– Nadel, J Infect Dis. 1996 TNF2
– Stuber, J Inflamm. 1996 TNF2

w i t h i n
TNFB2 (lymphotoxin)
e
– Stuber, Crit Care Med. 1996
o t y p e s TNFB2
s i s , l i k
–
g e n
Schroeder, Crit Care Med. 1999
t o r
TNFB2
s o f s e p
er s e c r e e d i at o r
HSP70-HOM, -2
t h e r i sk
Hyp
– Fang, Crit Care Med. 1999
m a t o r y m
s i n c r e s
IL-1 TaqI; IL-1ra
a e
.
fla m t y p e
TNFB2
c ti o n
– proin n o nf e
– Majetschak, Ann Surg. 1999 TNFB2
I - 1, g e a ft e r i
nd P A
Mira, JAMA. 1999
d e a t h TNF2

– TNF a d
– Hubacek, 2000 CD14
Lorenz, 2000
p s i s a n TLR2
–
v e r e
Waterer, 2001 s e TNF2; TNFB2
–
of s e
Appoloni, 2001 TNF2
– Hubacek, 2001 LBP
– Lorenz, 2002 TLR4
– Mira, 2002 PAI-1\
– Russell and Walley (abstracts) TNF2, TNFB2, IL-1RA, IL-6, and others

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Incidence of Sepsis by Chronic Health Conditions
•55.5% have at least 1 comorbidity
Comorbidity Occurrence (%)
– COPD 12.3
– Neoplasm (nonmetastatatic) 11.6
– HIV disease 6.3
– Chronic hepatic disease 4.5
– Chronic renal disease 5.4
– Neoplasm (metastatic) 5.3
– Complicated diabetes 3.2
Angus DC et al. Crit Care Med. 2001;29:1303-1310.

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Organ Failure and Mortality
90
1 2 3 4 or more
80 76.2
73.6
70 64.5
60
Percentage

50 44.3
40

30
20.7 21.2
20

10 4.7
1
0
Occurrence (%) by organ Mortality (%) by organ
failure failure

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Site of Infection
50
44 Respiratory
45

40 Bacteremia, site
Percentage of occurence

unspecified
35 Genitourinary
30
Abdominal
25

20 Wound and soft tissue

17.3
15 Device related
9.1 8.6
10 6.6 Central nervous system
5 2.2
0.8 0.6
Endocarditis
0
Site of infection (%)
Angus DC et al. Crit Care Med. 2001;29:1303-1310.
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Microbiology of Sepsis

Martin GS, et al. NEJM. 2003;348:1546.

Society of Critical Care Medicine ©2014 18

Overview
•Definitions
•Epidemiology
– Incidence of sepsis
– Predisposing factors for sepsis
– Risk factors for mortality due to sepsis
•Pathophysiology
•Management
•Summary
Society of Critical Care Medicine ©2014 19
Pathophysiology
•Susceptibility to sepsis is influenced by underlying host
response rather than individual pathogen characteristics.
– “… results from a harmful or damaging host response to
infection”
– Cohen J. Nature. 2002.
– “… an uncontrolled inflammatory response”
Hotchkiss RS and Karl IE. N Engl J Med. 2003.
•Innate immune mechanisms that protect humans against
infections may be detrimental.
•When does a normal host response become abnormal,
dysregulated, and uncontrolled?
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Pathways Leading to Sepsis: Why Does It Occur?
•Mediated via the monocyte-macrophage
system
– Part of the innate immune response and first line
of defense
– Important part of the normal host response
– Leads to activation of inflammatory and
coagulation cascade
•Mediated via endothelium activation
•Epithelial disease
Society of Critical Care Medicine ©2014 21
How Do Cells of the Innate Immune System
Recognize Pathogens?
•Pathogen-associated molecular patterns
(PAMPs) are components within microbes that
are recognized by the innate immune system.
– Gram-negative bacteria
• Lipopolysaccharide (LPS or endotoxin)
• Embedded in the outer lipid bilayer
– Gram-positive bacteria
• Peptidoglycan and lipoteichoic acid in cell wall

Society of Critical Care Medicine ©2014 22

Host Recognition of Cell Surface Receptors

Cohen J. Nature. 2002;420:885-891.

Society of Critical Care Medicine ©2014 23

Both Inflammatory and Coagulation Cascades Are
Activated
• Several mechanisms for
activation of coagulation
cascade exist.
• Endothelium also plays
an important role in
activation of
inflammatory and
coagulation cascades.
• Various autocrine and
paracrine loops are
activated.
Aird WC. Blood. 2003.

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Imbalance Between Procoagulant and Anticoagulant
Response
• Decrease in levels of
natural anticoagulants
(protein C, anti-
thrombin, tissue factor
pathway inhibitor)
• Activated protein C
levels are increased
• Enhanced coagulation

Cohen J. Nature. 2002;420:885-891.

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Microbial Components Activate Several Cascades
Simultaneously to Mediate Findings of Sepsis

Cohen J. Nature. 2002;420:885-891.

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Anti-Inflammatory Response
•Cytokines include
– IL-10
– IL-1 receptor antagonists
– TNF soluble receptors
•May play an important role in dampening the
proinflammatory response

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Hypothetical Model of Sepsis
Individual immune response
•Age
•Chronic health conditions
•Genetic factors
•Virulence of organism
•Inoculum size

Hotchkiss RS and Karl IE. N Engl J Med. 2003;348:138-150.

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Hypothetical Model of Sepsis
• Robust hyperimmune
response is important,
but…
• Exuberant response may
be detrimental.
• Response may be blunted
and followed by a
hypoimmune response in
older subjects with chronic
health conditions.

Hotchkiss RS and Karl IE. N Engl J Med. 2003;348:138-150.

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What Mechanisms Mediate End-Organ Dysfunction
During Sepsis?
• Tissue hypoperfusion and
hypoxia
• Lysosomal enzymes
released by neutrophils
• Cellular dysoxia (inability
to use available oxygen)
• Nitric oxide may mediate
cardiac dysfunction

Society of Critical Care Medicine ©2014 30

Pathophysiology of Severe Sepsis

Angus DC, van der Poll T. NEJM 2013;369:840-51.

Society of Critical Care Medicine ©2014 31

Overview
•Definitions
•Epidemiology
– Incidence of sepsis
– Predisposing factors for sepsis
– Risk factors for mortality due to sepsis
•Pathophysiology
•Management
•Summary
Society of Critical Care Medicine ©2014 32
 February 2013

Society of Critical Care Medicine ©2014 33

Management of Severe Sepsis and Septic Shock
•Anti-infectives and Source Control
•Hemodynamic resuscitation
– Early goal-directed therapy
– Fluids – crystalloids preferred
– Vasopressors – norepinephrine 1st choice
•Corticosteroids for refractory shock
•Drotrecogin alfa-activated: withdrawn from
market

Society of Critical Care Medicine ©2014 34

                                 

Society of Critical Care Medicine ©2014

Kumar A, et al. Crit Care Med. 2006;34:1589.

35
Antimicrobial Therapy
•Goal is to administer effective IV antimicrobials
within the first hour of recognition of septic
shock (1B) and severe sepsis w/o shock (1C).

Dellinger RP, et al. Crit Care Med. 2013;41:580-637.

Society of Critical Care Medicine ©2014 36

Hemodynamics of Sepsis
•Hypotension with normal or high cardiac
output
•Vascular dysfunction
• Hypotension
• Peripheral vasodilation
• Decreased systemic vascular resistance
•Myocardial dysfunction
• Decreased ejection fraction
• LV dilation to preserve stroke volume and CO
• Time course: 24-48 hours
Dellinger RP, et al. Crit Care Med 2003;31:946-55.

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Hemodynamic Derangements in Septic Shock

Dellinger RP et al. Crit Care Med. 2004;32:858-873.

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Hemodynamic Derangements in Septic Shock

Dellinger RP et al. Crit Care Med. 2004;32:858-873.

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 Initial Resuscitation
•Protocolized, quantitative resuscitation with the
following goals during the first 6 hours:
– CVP 8-12 mm Hg
– MAP > 65 mm Hg
– UOP > 0.5 mL/kg/hr
– ScvO2 70% or SvO2 65% (1C)
•In patients with elevated lactate levels, target
resuscitation to normalize lactate (2C)
Dellinger RP, et al. Crit Care Med 2013;41:580-637.

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 Fluid Therapy
•Crystalloids recommended as initial fluid of
choice for resuscitation in severe sepsis and
septic shock (1B).
•Albumin can be used when patients require
substantial amounts of crystalloids (2C).
•Hydroxyethyl starches should not be used (1B).
– VISEP, CRYSTMAS, 6S, and CHEST trials
– Increased incidence of renal failure and mortality
Dellinger RP, et al. Crit Care Med 2013;41:580-637.

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 Vasopressor Therapy
•Norepinephrine recommended as first choice
vasopressor (1B).
•Dopamine as an alternative in highly selected
patients at very low risk of tachyarrhythmias and
with relative or absolute bradycardia (2C).

Dellinger RP, et al. CCM. 2013.

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 Vasopressor Therapy
•Add or substitute epinephrine for NE when an
additional agent is needed to maintain adequate
BP (2B).
•Vasopressin up to 0.03 U/min can be added to
NE (UG); not recommended as single initial
vasopressor.

Dellinger RP, et al.. Crit Care Med. 2013;41:580-637.

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• Not using IV hydrocortisone to treat adult septic shock
if adequate fluid resuscitation and vasopressors are
able to restore hemodynamic stability; if not, use IV
hydrocortisone 200 mg/day (2C).
• Not using ACTH stim test to identify patients with septic
shock who should receive hydrocortisone (2B).
• Hydrocortisone should be tapered when vasopressors
are no longer required (2D).

Dellinger RP, et al. Crit Care Med. 2013;41:580-637.

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Surviving Sepsis Guidelines 2012
• Supportive Therapies:
– Lung protective ventilation (1A), conservative fluid
therapy (1C), recruitment maneuvers for
refractory hypoxemia (2C)
– Targeted sedation (1B), short course NMB for
ARDS (2C)
– Platelets only if <10,000/mm3 if no apparent
bleeding) (2D)
– Immunoglobulins: No (2B)
Dellinger RP, et al. Crit Care Med. 2013;41:580-637.

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Surviving Sepsis Guidelines 2012
• Supportive Therapies:
– Target glucose levels < 180 mg/dL (1A)
– Renal replacement therapy and HD equivalent
(2B)
– VAP, DVT/PE, stress ulcer prophylaxis, enteral
nutrition
– Setting goals of care

Dellinger RP, et al. Crit Care Med. 2013;41:580-637.

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Resuscitation Trials in Septic Shock: 2014

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ProCESS Trial
•Multicenter RCT, 31 EDs, n=1341
•3 groups (first 6 hours):
– Protocol-based EGDT
– Protocol-based Standard Therapy without CVC
– inotropes or blood transfusions or Usual Care
•Primary outcome: 60-d hospital mortality
•Secondary outcomes:
– 90-d all-cause mortality and at 1 year
– Type, degree and duration of organ dysfunction
– ICU and hospital LOS
– Hospital discharge disposition
NEJM. 2014; March 18

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ProCESS: No Outcome Benefit

NEJM. 2014; March 18

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Albumin Replacement in Severe Sepsis or Septic Shock
(ALBIOS)
•Multicenter, open-label, 100 ICUs, n=1818
•20% albumin + crystalloids vs. crystalloid alone
•Target serum albumin 3.0 g/dL in albumin group
•Primary outcome: 28-d mortality
•Secondary outcomes:
– 90-d all-cause mortality
– Type and degree of organ dysfunction
– ICU and hospital LOS
Caironi P, et al. ALBIOS Study Group
NEJM 2014; March 18

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Albumin Replacement in Severe Sepsis or Septic Shock

• No survival
benefit with
albumin +
crystalloids.

NEJM. 2014; March 18

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Summary
•Morbidity and mortality rates from severe sepsis and
septic shock remain high.
•Early identification of patients with sepsis-induced
tissue hypoperfusion is the highest priority.
•Protocolized approach to identification and treatment
of patients with severe sepsis is crucial.
•The most recent Surviving Sepsis Campaign Guidelines
2012 is an excellent resource for key evidenced-based
recommendations.

Society of Critical Care Medicine ©2014 52

Questions?

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