Ramphal sepsis.ppt

8/10/2019 Ramphal sepsis.ppt

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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

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Ramphal sepsis.ppt