Transcript No Slide Title

Sepsis:
A New Look at an Old Problem
Nathan Shapiro, MD, MPH
Beth Israel Deaconess Medical Center
Harvard Medical School
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. 2001;29:7:1303-1309
Severe Sepsis: Comparison With
Other Major Diseases
Incidence of Severe Sepsis
Mortality of Severe Sepsis
300
250,000
200
150
100
50
0
AIDS* Colon Breast CHF† Severe
Cancer§
Sepsis‡
†National
200,000
Deaths/Year
Cases/100,000
250
150,000
100,000
50,000
0
AIDS*
Breast AMI†
Cancer§
Severe
Sepsis‡
Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association.
2000. ‡Angus DC et al. Crit Care Med. 2001 (In Press).
What is sepsis?
Host Infection
Systemic Inflammatory Response
Pro-inflammatory/Anti Inflammatory Activity
Accelerated Inflammatory Cascade
Sepsis Syndromes
Sepsis Definitions
Systemic Inflammatory Response Syndrome:
(SIRS): two or more of the following
1.
2.
3.
4.
T>38 or <36
HR > 90 beats/min
RR>20 beats/min or pCo2<32 torr
WBC>12,000 or < 4,000 or >10% bands
SEPSIS – SIRS due to an infection
ACCM/SCCM Consensus Conference:Chest :1992:20:6
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)
The Natural History of the Systemic
Inflammatory Response Syndrome
• 3708 patients, multi-center prospective study
in ICU/inpatient population
Syndrome
SIRS
Sepsis
Severe Sepsis
Septic Shock
Mortality
2.2% (2.3-4.1)
2%
(1.0-3.5)
9%
(7.2-10.7)
15% (9.5-20.3)
Rangel-Frausto et. al. JAMA:1995:273:117-123.
Sepsis Syndromes in the Emergency
Department
• 3179 patients, prospective, ED based study
Syndrome
No SIRS
SIRS/Sepsis
Severe Sepsis
Septic Shock
Mortality
3.2% (2.3-4.1%)
8%
(1.1-3.5%)
10% (7.4-10.8%)
27% (16.5-41.2%)
Shapiro et al. 2001 SCCM Meeting
“Patients die of
complications of their
disease, rather than the
disease itself”
Sir William Osler
Mediators of Sepsis
Anti-Inflammatory
IL-4
IL-6 (both)
IL-10
IL-11
IL-13
LPS
TNF
IL-1
IL-6/IL-8
NO,PAF, others
Local Inflammation
(low levels)
Sepsis
(medium levels)
Severe Sepsis
(high levels)
Approach to Sepsis
• Recognition of SIRS/Sepsis
• Identify etiology
• Early and Aggressive Treatment
“Sick, or not sick?
That is the question!”
(Adapted from) Shakespeare
“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)
What are the RED FLAGS
in Emergency
Department patients with
sepsis?
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
Patient Enrollment
3,301
Patient Encounters
122 (4%)
missed
3,179 (96%)
Enrolled
1/3
2/3
2,070
Derivation Set
Regression and
Prediction Rule
Visits
randomly
assigned
1,109
Validation Set
Independent Predictors Identified by Multivariate Analysis
__________________________________________________
Variable
Odds Ratio
95% CI
Points
__________________________________________________
Terminal illness (<30d)
Tachypnea or hypoxia
Platelets < 150,000 /mm3
Bands > 5%
Age > 65
Suspected pneumonia
Nursing home resident
Septic Shock
Altered mental status
6.3
2.6
2.6
2.3
2.3
2.0
1.9
2.6
1.7
(3.7 to 10.4)
(1.6 to 4.2)
(1.6 to 4.4)
(1.4 to 3.5)
(1.4 to 3.7)
(1.3 to 3.2)
(1.2 to 3.1)
(1.0 to 3.3)
(1.1 to 2.7)
Shapiro et al/ Critical Care Medicine. March 2003
6
3
3
3
3
2
2
3
2
**ROC Area = .81
Derivation
Validation
Mortality by MEDS score
60%
51%
50%
Mortality %
39%
40%
30%
18%16%
20%
10%
8% 9.1%
4.7%
.6%.7% 2.3%
0%
0-4
5-7
8-12
MEDS score
12-15
>15
ED Predictors of death from Sepsis
Host Status
• Terminal illness (<30d)
• Age > 65
• Nursing home resident
Infection Type
• Suspected pneumonia
Findings:
• **Tachypnea or hypoxia
• **Septic Shock
• Altered mental status
Lab Abnormalities
• Platelets < 150,000 /mm3
• Bands > 5%
Therapy
“Over 13,000 patients have been enrolled in 23
multi-center, placebo-controlled, clinical
trials……results 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. 1999:13:2.
Sepsis
Systemic
Inflammation
Coagulation
Protein C
Infection
Sepsis: A Network of
Cascading Events
PROINFLAMMATORY
MEDIATORS
INFLAMMATION
Activated
Protein C
ANTI-INFLAMMATORY
MEDIATORS
T
TM
Protein C
ENDOTHELIAL
INJURY
Activated
Protein C
INFECTION
COAGULATION
TAF-1
T-PA
FIBRINOLYSIS
TF
PAI-1
Endogenous Activated Protein C Modulates Coagulation,
Fibrinolysis, and Inflammation in
Severe Sepsis
Homeostasis
Carvalho AC et al. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock. 1996;5:223-8; Vervloet MG et al. Semin
Thromb Hemost. 1998;24:33-44.
Recombinant Human Activated
Protein C
• 1690 patients, double blind, placebo
controlled
• Inclusion:
– known/suspected sepsis
– > 3 SIRS criteria
– dysfunction > 1 organ systems
Bernard et.al. NEJM. March 8, 2001:344:10:699-709.
Results
Mortality
Control
30.8%
VS
Protein C Group
24.7%
6.1% absolute reduction in DEATH
(Number needed to treat = 17)
Bernard et.al. NEJM. March 8, 2001:344:10:699-709.
APC “PROS”
• Well designed RANDOMIZED, DOUBLE
BLIND, MULTICENTER, PLACEBO
CONTROLLED study showing benefit in
meeting primary objective
• Makes good biological sense
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
1Cost-Benefit
• All patients:
$27,936 per life-year
• APACHE II > 25
• APACHE II < 24
$24,484 per life-year
$575,054 per life-year
1Manns et al. NEJM:347:13:993-1000