sepsis richard p. wenzel, m.d., m.sc. professor and chairman department of internal medicine medical...

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