SepsisSepsis
Richard P. Wenzel, M.D., M.Sc.
Professor and Chairman
Department of Internal Medicine
Medical College of Virginia
Virginia Commonwealth University
Semmelweis’ Data - Impact of Poor Handwashing Practices
0
1
2
3
4
5
6
7
8
Cru
de
mor
tali
ty (
%)
8% 2%
Physician Med/Students Midwives
• attributable mortality: 8%-2%=6%
• YLL: Age 55 - Age 20 = 35 yearsper death
• Attributable burden: 6 x 35 = 210 years lost per 100 deliveries
SIRS
Fever or Hypothermia (>38º or 36º)
Tachycardia (>90)
Tachypnea (>20)
Hi/Low WBC (>12, <4, >10% bands)
Bone et alChest 1992; 101: 1644-55
Sepsis Definitions
sepsissepsissevereseveresepsissepsis
septic septic shockshock
SIRS ( 2) fever or SIRS Sepsis Severe sepsishypothermia + + +tachycardia (>90) infection hypotension hypoperfusiontachypnea (>20) or +H./low WBC or hypoperfusion hypotension 10% bands despite 500 ml
bolus fluid
Estimates of the Impact of Sepsis Syndromes Annually in U.S.
Sepsis200,000
Severe sepsis200,000
Septicshock
200,000
Mortality Deaths
- 46% 92,000
- 20% 40,000
- 16% 32,000
600,000 cases/yr 164,000 deaths/yr
Geographic Distributionof SCOPE Hospitals
Rank Order of Nosocomial Bloodstream Infections and Mortality
SCOPE Surveillance System
40
30
20
10
CNS S.aureus Enterococcus Candida
n=3908 n=1928 n=1354 n=934
pro
por
tion
of
BS
I (%
)
0
proportion
crude mortality
crudemortality (%)
32 21 16 25
11 32 8 40
Edmond et alCID 1999
Attributable Mortality: The Promise of Better Antimicrobial Therapy
8070
60
50
40
30
20
10
all-
cau
se (
cru
de)
mor
talit
y -
per
cen
t-
Attributable mortality of resistance geneAttributable mortality of infectionMortality from underlying disease
infectionandno Rx
infection and Rx
infection and no Rx
resistancegene
resistancegene
infectionand Rx
effect ofexisting Rx
1 2 3 4 5 scenarios
effect ofexisting Rx
SCOPE: Years of Life Lost from Nosocomial Bloodstream Infections
0
500
1000
1500
2000
2500
10 15 20 25 30Attributable Mortality (%)
YLL (x 1000)
10% totalnosoinf rate
5% totalnoso inf rate
2 1/2% total nosoinf rate
Mean age death - 60 yrAssume normal lifespan - 70 yr
350
525
700
875
1050
175262.5
350437.5
525
87.5 131.25 175 218.75 262.5
Conjugative Plasmids in the Pre-Antibiotic Era
E.D.G. Murray - Enterobacteria gene 1917-54
Origin - N.Am., Europe, India, Mid East, Russia
Strains - Salmonella (48%); Shigella (32%),
E. coli (7%) 1917-41
• Genetic transfer function (plasmids) - 24%
• AMP in 2%; tetra 9%
• No plasmids had resistance genes
R R
Hughes & DattaNature 1981; 302:725
Coagulase-Negative Staph Nosocomial Bacteremia:
Methicillin Resistance
Resistant Susceptible
17%
83%
N=6,047
Methicillin-Resistant S. aureus
N= 3,567
SCOPE, 1995-2000.
Region %methicillin resistance
Northeast 35Northwest 22Southeast 49Southwest 30
All 39
Nosocomial Enterococcal Bacteremia:Vancomycin Susceptibility by Species
R
RR
E. faecalis (n=378)3% vancomycin resistant 46% vancomycin resistant
E. faecium (n=129)
Nosocomial Candidemia
Other6%
C. parapsilosis
22%
C. krusei6%
C. glabrata40%
C. tropicalis26%
N=1,698 SCOPE, 1995-2000
R
0%
20%
40%
60%
80%
100%
SCOPE Project:Distribution of Candida Nosocomial BSIs
0
20
40
60
0
20
40
60
0
20
40
60
0
20
40
60
56
17 3
70
15 1
46
26
4
51
184
C. albicans
C. glabrata
C. krusei
Edmond et al CID 1999
SCOPE: Nosocomial Bloodstream Infections
proportionoccurringin ICUs
n=3908 n=1928 n=1354 n=934
59 44 53 57
Edmond et al CID 1999
ICU BSI: Increased Mortality with Inadequate Antimicrobial Therapy
Risk for death
AOR
Inadeq. Rx 6.9
Vasopres 3.0
No. organ fail 2.3
Risk for inad. Rx
Candida 52
Prior AB 2.1
ALB 1.3
CVC days 1.03
Adequate Inadequate (n=345) (n=147) therapy
29%
62%
Mor
tali
ty (
%)
Ibrahim et al Chest 2000; 118: 146-55
0
200
400
600
800
1000
1200
1400
1600
1800
Time course of NFkB binding activity
Days 1 2 3 4 5 6 8 10 14
% N
Fk
B b
ind
ing
acti
vity
(d
ay 1
=10
0%)
NFkB-binding activity (EMSA)
Böher et al1997 J Clin Invest100:972-985
Genetic Factors in Septic Shock
TNFZ: a single base pair change
TNF gene promoter
HLA class III genes
Chromosome 6
Frequency- TNF gene promoter Control Septic shock P(n=87) (n=89)
Any poly-morphism 25 43 .008
TNFZ 16 35 .002
Outcome - Septic Shock (n=89)Lived Died P(n=41) (n=48)
Any poly-morphism 14(34) 29(61) .01TNFZ 10 25 .008
Mira et al JAMA 1999; 282:561-8
Sepsis: Variables Predicting Mortality
Host: genetics
co-morbidities
temperature
Organism: Ps. Aeruginosa; Candida
2 inf vs 1
Polymicrobial vs Unimicrobial
Therapy: Appropriate Antibiotics
Trained ICU team
Two Antimicrobial ImpregnatedCentral Venous Catheters
Multicenter (n=12) study
Minocycline - SilverRifampin Sulfadiazine
No. 356 382BSI 1 (0.3%) 13 (3.4%)
12 inf/~370 or 32 inf/1000 prevented
Darouiche et alNEJM 1999; 340: 1-8
The Effect of an Alcohol-based Hand Disinfectant on Handwashing Compliance in the Medical ICU
0
10
20
30
40
50
Before Patient Contact After Patient Contact
173 188
112
10
2216
2519
41
23
48
122
96Baseline After
EducationAlcohol Dispenser
106
79
93
1:4 ratio 1:1 ratio
(no. of washes/no of opportunities)
%
Bischoffet alIDSA 1998
Sepsis and Death After Hi-Dose Growth Hormone in ICU Patients
0
5
10
15
20
25
30
35
40
45
G.H.placebo
RP=1.9 (1.3-2.9) RP=2.4 (1.6-3.5)p<0.001 p<0.001
Mor
tali
ty (p
erce
nt)
39% 20% 44% 18%
(n=119) (n=123) (n=139) (n=141)
Finnish study Multination study32% vs 16% 26% vs 15%
Proportion ofdeaths fromseptic shock/uncont.infection
Takala et alNEJM 1999; 341:785
Hypocalcemia and Sepsis
Malnourished patient: Vit D intake
and Albumen ( total Ca ++)
Allealosis: prot binding, ionized Ca ++
Sepsis: FFA cause prot binding
cytokines cause PTH
liver, renal dysfunctions:
hydroxylation Vit D10% chelated10% chelated
50% ionized50% ionized
40% protein40% protein boundbound
JAMA 1986; 256: 1924Crit Care Med 2000; 28:266
Conc: Vit DPTH
Adrenal Insufficiency in Refractory (4 hours) Hypotension Among ICU Patients
0
5
10
15
20
25
30
35
40
45
50
per
cen
t su
bje
cts
46% 0% 40% 0%
Peak 20 g/ml Baselineafter 1 g ACTH 15 g/ml
R.H. (n=15)Controls (n=9)
Beale et alChest 1999; 4:(S-2)366S
Recombinant Human Activated Protein C and Sepsis
APC • antithrombotic
• profibrinolytic
• antiinflammatory
Prot C to APC
impaired in sepsis
HAPC - PHASE II dose-dep decrease
• d-dimer, IL-6
• coag; inflamArterioscler Throm 1992; 2:135 Intensive Care Med 1998; S77
Recombinant Human Activated Protein C and Severe Sepsis: Phase II Study
Placebo (41)
2 low doses (51) 12 and 18 mcg/kg/h
2 hi-doses (39) 24 and 30 mcg/kg/h
hi-dose: reduced d-dimer (p<0.01)
trend platelets
Mortality: placebo (34%0
low dose (35%)
hi dose (21%)Hartman et al Intens Care Med 1998; S77
Therapy of Sepsis
• volume replacement !!• if BP remains low - pressors eg dopamine• if BP still low, r/o adrenal insufficiency, severe
acidosis hypocalcemia, hypocalcemia• correct pH to 72
• oxygen• best choice antibiotics ( I + D?)• rapid transfer to ICU with CCM trained experts
