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Sepsis
Reuben Ramphal M.D.Division of Infectious Diseases
University Of Florida
October 31, 2005 11:00
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Occurrence of Severe Sepsis
Annual incidence: ~750,000 cases in US
2.26 cases per 100 hospital discharges
51.1% received ICU care and 17.3% received IMC care Incidence and mortality increased with age
Case fatality rate: 28%
Economic burden $22,100 per case
~$16.7 billion nationally
Angus DC et al. 2001. Crit Care Med 29:1303-1310.
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Sepsis on the Rise Incidence projected to rise to 1.0 million
cases annually in US during the next decade
Aging population Increased awareness and diagnosis
Immunocompromised patients
Invasive procedures
Resistant pathogens
Angus DC et al. 2001. Crit Care Med 29:1303-1310.
Balk RA. 2000. Crit Care Clin 16(2):179-191
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Definitions
SIRS Sepsis SevereSepsis
SepticShockInfection
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Sepsis Sepsis
SIRS + infection
Severe sepsis Sepsis with organ dysfunction, hypoperfusion or
hypotension
Septic Shock
Sepsis with hypotension and perfusionabnormalities despite adequate volumereplacement
Bone, et al. 1992. Chest 101:1644-1655
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Mortality from SepsisMartin NEJM 2003
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Pathogenesis of Sepsis Interaction of specific Pathogen associated
molecular patterns (PAMPs--microbialligands) on organisms with specific receptorsToll like receptors (Tlrs) on animal cells
PAMPs Highly conserved parts of microbial molecules
Sepsis also caused by Interactions of superantigens with T- cells e.g. Somestaphylococcal and streptococcal toxins
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Innate Immune response Sepsis Interaction of a PAMP with a Tlr results in a
cellular cascade which leads to activation ofinnate immune mechanisms Message sent to nucleus resulting in transcription
of repressed genes
Antimicrobial peptide synthesis and release
Beginning of a specific adaptive antibody
response Release of Mediators of inflammation
Normally protective but some type ofdysregulation leads to signs of SEPSIS
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Akira and Hashino, Osaka University JID 2003
Microbial Ligands Recognized by TLR family
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Microbial Ligands and Tlr recognition
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Synthesis and release of effector molecules
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Pathogenesis of Severe Sepsis
Infection
Microbial Products(exotoxin/endotoxin)
Cellular Responses
OxidasesPlatelet
ActivationKinins
Complement
Coagulopathy/DICVascular/Organ System Injury
Multi-Organ Failure
Death
CoagulationActivation
CytokinesTNF, IL-1, IL-6
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Clinical effects of dysregulation of innate
immune responses Clinical sepsis
Fever
Hypoperfusion Hypotension Shock
Clotting Disseminated intravascularcoagulation
Renal failure Cardiac depression
Central nervous system depression
Acute respiratory Distress syndrome
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Most effective therapies Early recognition of preshock- tachynea
leading to respiratory alkalosis
Low Pco2, pH >7.45 Lots of Fluids-crystalloid or colloid
Antibiotics
Effective antibiotics Timely administration of Effective
antibiotics
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Effect of antibiotics on Survival from sepsis
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Independent risk factors for mortality for 136 patientswith Pseudomonas aeruginosabacteremia.
Risk factor OR (95% CI) P
Ineffective definitive antibiotic treatment 11.68 (2.5154.38) .002Ineffective empirical antibiotic treatment 4.61 (1.1818.09) .028
Presentation with septic shock 45.37 (10.19201.93)
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Timing of Antibiotic administration and mortalityDue Sepsis
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What constitutes adequate antibiotictherapy in Sepsis
Site of Infection if known helps to limit choicesie-intraabdominal, or necrotizing soft tissueinfection need for anaerobic coverage.
Lung most common site of documentedinfection
Resistance picture in hospital if hospital
acquired and in the community if communityacquired
Generally Gram positive and Gram negativecoverage
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Baseline Microbiology from a largeSeptic shock study
Per
centofPatients
0
5
10
15
20
2530
35
Placebo (N=840)
Drotrecogin Alfa(activated) (N=850)
NoIdentifiable
Microorganism
PureFungal
GramMixed
GramNegative
GramPositive
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Primary Sites of Infection in a recent largestudy of Septic shock
PercentofPatients
0
10
20
30
40
50
60
Placebo N=840
Drotrecogin Alfa
(activated) N=850
OtherSkinBloodUrinary
Tract
Intra-
Abdominal
Lung
Site of Infection
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Antibiotic Choices Given the world wide resistance issues
the most effective antibiotic choices tocover gram negatives would be
Fourth generation cephalosporins aminoglycoside
Carbapenems aminoglycoside
Pip-Tazobactam + an aminoglycoside
If the incidence of MRSA is high add ananti Staphylococcal agent --Vanco,Teicoplanin
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Effector mechanism based non antibiotic adjuncts to therapy
IL-1TNF
APC
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Nonantibiotic therapy of septic shock and sepsis
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Drotrecogin Alfa (Activated ProteinC)Reduced 28-Day All-Cause Mortality
0
5
10
15
20
25
30
35
30.8%
24.7%
Placebo(N=840)
DrotrecoginAlfa
(activated)(N=850)
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Optimum therapyof sepsis Antibiotics remain the most critical choice to
be made TIMELY, EFFECTIVE, BROAD SPECTRUM
Resistance issues need to be kept in mind
Modify antibiotics when organism is known
A large number of patients with the sepsissyndrome will not have an organism cultured
Agents designed to neutralize the biologicactions of the inflammatory response may beadditive, but it will likely require multipleagents