Sepsis:

1
Sepsis A New Look at an Old Problem
Nathan Shapiro, MD, MPH Beth Israel Deaconess
Medical Center Harvard Medical School
2
Sepsis

• 750,000 cases per year in US
• Mortality ranges 10-60
• 215,000 deaths/year
• More than 640 deaths/day in US
• 22,000 per case
• 16.7 billion per year in US

Angus et al. Crit Care Med. 20012971303-1309
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Severe Sepsis Comparison With Other Major
Diseases
Incidence of Severe Sepsis
Mortality of Severe Sepsis
Cases/100,000
Severe Sepsis
AIDS
AMI
Breast Cancer
Breast
AIDS
Colon
CHF
Severe Sepsis
Cancer
National Center for Health Statistics, 2001.
American Cancer Society, 2001. American Heart
Association. 2000. Angus DC et al. Crit Care
Med. 2001 (In Press).
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What is sepsis?
Host Infection Systemic Inflammatory
Response Pro-inflammatory/Anti Inflammatory
Activity Accelerated Inflammatory Cascade Sepsis
Syndromes
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Sepsis Definitions

• Systemic Inflammatory Response Syndrome
• (SIRS) two or more of the following
• Tgt38 or lt36
• HR gt 90 beats/min
• RRgt20 beats/min or pCo2lt32 torr
• WBCgt12,000 or lt 4,000 or gt10 bands
• SEPSIS SIRS due to an infection

ACCM/SCCM Consensus ConferenceChest 1992206
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Sepsis Definitions

• SEVERE SEPSIS - Sepsis Organ Dysfunction,
• signs of organ dysfunction in the following
  systems
• Cardiovascular
• Renal
• Respiratory
• Hepatic
• Hemostasis
• CNS
• Unexplained metabolic acidosis
• SEPTIC SHOCK Severe Sepsis hypotension
  (despite adequate fluid resuscitation)

7
SIRS
sepsis
severe sepsis
septic shock
Multisystem Organ Dysfunction
8
The Natural History of the Systemic Inflammatory
Response Syndrome

• 3708 patients, multi-center prospective study in
  ICU/inpatient population
• Syndrome Mortality
• SIRS 2.2 (2.3-4.1)
• Sepsis 2 (1.0-3.5)
• Severe Sepsis 9 (7.2-10.7)
• Septic Shock 15 (9.5-20.3)

Rangel-Frausto et. al. JAMA1995273117-123.
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Sepsis Syndromes in the Emergency Department

• 3179 patients, prospective, ED based study
• Syndrome Mortality
• No SIRS 3.2 (2.3-4.1)
• SIRS/Sepsis 8 (1.1-3.5)
• Severe Sepsis 10 (7.4-10.8)
• Septic Shock 27 (16.5-41.2)

Shapiro et al. 2001 SCCM Meeting
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Patients die of complications of their disease,
rather than the disease itself

• Sir William Osler

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Mediators of Sepsis
LPS TNF IL-1 IL-6/IL-8 NO,PAF, others
Anti-Inflammatory IL-4 IL-6 (both) IL-10 IL-11 IL-
13
Local Inflammation Sepsis Severe
Sepsis (low levels) (medium levels) (high
levels)
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Approach to Sepsis

• Recognition of SIRS/Sepsis
• Identify etiology
• Early and Aggressive Treatment

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Sick, or not sick?That is the question!
(Adapted from) Shakespeare
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Hectic Fevers at its inception is difficult to
recognize, but easy to treat Left untended, it
becomes easy to recognize, but difficult to
treat.
Niccollo Machievielli, in The Prince(1513)
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What are the RED FLAGS in Emergency Department
patients with sepsis?
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Mortality in Emergency Department Sepsis (MEDS)
Score

• Objective To identify predictors of death from
  sepsis present in Emergency Department (ED)
  patients
• Prospective Study of 3179 ED patients admitted to
  hospital with suspected infection
• Logistic regression to identify predictors of
  death

Shapiro et al/ Critical Care Medicine. March 2003
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Patient Enrollment
122 (4) missed
3,179 (96) Enrolled
1/3
2/3
Visits randomly assigned
2,070 Derivation Set
1,109 Validation Set
Regression and Prediction Rule
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Independent Predictors Identified by Multivariate
Analysis _________________________________________
_________
Variable Odds Ratio 95 CI
Points ___________________________________________
_______ Terminal illness (lt30d) 6.3
(3.7 to 10.4) 6 Tachypnea or hypoxia 2.6
(1.6 to 4.2) 3 Platelets lt 150,000 /mm3 2.6
(1.6 to 4.4) 3 Bands gt 5
2.3 (1.4 to 3.5) 3 Age gt 65 2.3 (1.4
to 3.7) 3 Suspected pneumonia 2.0 (1.3 to
3.2) 2 Nursing home resident 1.9 (1.2
to 3.1) 2 Septic Shock 2.6
(1.0 to 3.3) 3 Altered mental status
1.7 (1.1 to 2.7) 2

Shapiro et al/ Critical Care Medicine. March 2003
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ROC Area .81
Derivation
Validation
Mortality by MEDS score
60
51
50
39
40
Mortality
30
18
16
20
8
9.1
10
4.7
2.3
.6
.7
0
0-4
5-7
8-12
12-15
gt15
MEDS score
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ED Predictors of death from Sepsis

• Host Status
• Terminal illness (lt30d)
• Age gt 65
• Nursing home resident
• Infection Type
• Suspected pneumonia

• Findings
• Tachypnea or hypoxia
• Septic Shock
• Altered mental status
• Lab Abnormalities
• Platelets lt 150,000 /mm3
• Bands gt 5

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Therapy

• Over 13,000 patients have been enrolled in 23
  multi-center, placebo-controlled, clinical
  trialsresults have been generally disappointing
  with some spectacular failures
• From Clinical Trials for Severe Sepsis. Past
  Failures and Future Hopes, 1999

Opal et al. Infectious Disease Clinics of North
America. 1999132.
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Sepsis
Systemic Inflammation
Coagulation
Protein C
Infection
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Sepsis A Network of Cascading Events
PROINFLAMMATORY MEDIATORS
ANTI-INFLAMMATORY MEDIATORS
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Endogenous Activated Protein C Modulates
Coagulation, Fibrinolysis, and Inflammation in
Severe Sepsis
Fibrinolytic
Anti-Inflammatory
Pro-Coagulant
Pro-Inflammatory
Homeostasis
Carvalho AC et al. J Crit Illness. 1994951-75
Kidokoro A et al. Shock. 19965223-8 Vervloet
MG et al. Semin Thromb Hemost. 19982433-44.
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Recombinant Human Activated Protein C

• 1690 patients, double blind, placebo controlled
• Inclusion
• known/suspected sepsis
• gt 3 SIRS criteria
• dysfunction gt 1 organ systems

Bernard et.al. NEJM. March 8, 200134410699-709.
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Results

• Mortality
• Control Protein C Group
• 30.8 VS 24.7
• 6.1 absolute reduction in DEATH
• (Number needed to treat 17)

Bernard et.al. NEJM. March 8, 200134410699-709.
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APC PROS

• Well designed RANDOMIZED, DOUBLE BLIND,
  MULTICENTER, PLACEBO CONTROLLED study showing
  benefit in meeting primary objective
• Makes good biological sense

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APC CONS

• Single Study
• Numerous exclusion criteria
• Altered exclusion criteria mid-study
• Very expensive
• Unclear benefit in patients with lower APACHE
  Scores

FDA mandated follow-up study (lower acuity)
starting soon
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1Cost-Benefit

• All patients 27,936 per life-year
• APACHE II gt 25 24,484 per life-year
• APACHE II lt 24 575,054 per life-year

1Manns et al. NEJM34713993-1000