severe sepsis nejm 2013 ppt2
TRANSCRIPT
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Review Article: Critical Care Medicine
Severe Sepsis and Septic Shock
LOGO
Derek C. Angus, M.D., M.P.H., and Tom vander Poll, M.D., Ph.D.
N Engl J MedVolume 369(9):840-851August 29, 2013
,
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Introduction
Incidence
Clinical feature
Outcome
at ogenes sTreatment
New strategies
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Incidence
Incidence of severe sepsis
depends on how acute organ dysfunction isdefined
whether that dysfunction is attributed to an
underlying infection.Organ dysfunction is often defined by the
provision of supportive therapy (e.g.,
mechanical ventilation),
count the treated incidence rather than theactual incidence.
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Incidence
High-income countries, Modern ICU
Similar rates of sepsis
2% of patients admitted to the hospital
10% of patients admitted to ICU
,Other
Unknown
Estimated up to 19 million cases worldwideper year
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Incidence
Community-acquired
Health careassociated
Pneumonia-Half of cases
IAI, UTI
1/3 cases-> Blood culture positive1/3 cases-> All culture negative
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Incidence
Staphylococcus aureus
Streptococcus pneumoniae
Escherichia coli
62%
Klebsiella speciesPseudomonas aeruginosa
Fungus 19%
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Risk factors
Risk factors for severe sepsis
Chronic diseases (AIDS, COPD, cancers)
Use of immunosuppressive agents.
Risk factors for organ dysfunction
ess we s u e
Causative organism
Genetic composition
Underlying health status,
Preexisting organ function
The timeliness of therapeutic intervention
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Polymorphisms in genes encoding proteins
implicated in the pathogenesis of sepsis Cytokines and other mediators
Innate immunit coa ulation and fibrinol sis.
Heterogeneity of the patient populations
Findings are often inconsistent
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Clinical manifestation
Highly variable
Site of infection, organism, the pattern of acuteorgan dysfunction, the underlying health status
dysfunction may be subtle
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Acute organ dysfunction
Respiratory
ARDS, hypoxemia with bilateral infiltrates of
noncardiac origin.
Cardiovascular
Myocardial dysfunction
Central nervous system dysfunction
Obtundation or delirium. EEG: nonfocal encephalopathy
Polyneuropathy and myopathy
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Acute organ dysfunction
Renal
decreasing urine output
Increasing serum creatinine level
Paralytic ileus
evate am notrans erase eve sAltered glycemic control
Thrombocytopenia
Disseminated intravascular coagulation,
Adrenal dysfunction
Euthyroid sick syndrome
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Outcome
Severe sepsis
Mortality: 20 to 30%
Patients who survive to hospital dischargeafter sepsis remain at increased risk for
.
Impaired physical or neurocognitive
functioning
Mood disorders Low quality of life
Causal role of sepsis in such subsequent
disorders has been difficult
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Pathophysiology
Overly exuberant inflammation
directed at eliminating invading pathogens
Collateral tissue damage
Compensatory antiinflammatory response
Limiting local and systemic tissue injury
Enhanced susceptibility to secondary
infections.
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Toll-like receptors
C-type lectin receptorsRetinoic acid inducible gene
e receptors
Nucleotide-binding
oligomerization domainlikereceptors
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High-mobility group protein B1S100 proteinsExtracellular RNA, DNA, histones
Sepsis
Trauma
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proinflammatory effect
Antiinflammatory effect
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LeukocyteComplement
Regulatory T cellMyeloid suppressor cell
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In animal models Vagotomy -> increases susceptibility to endotoxin shock Stimulation of the efferent vagus nerve or 7 cholinergic
receptors -> attenuates systemic inflammation.
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Immunosuppression in sepsis
Patients who survive early sepsis butremain dependent on intensive care have
evidence of immunosuppression Reduced expression of HLA-DR on myeloid
ll
Reduced responsiveness of blood leukocytesto pathogens in patients with sepsis
Spleen -> Strong functional impairments ofsplenocytes
Lung -> enhanced expression of ligands for T-
cell inhibitory receptors on parenchymal cells.
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Mechanisms of organ failure
Only partially elucidated
Impaired tissue oxygenation plays a key
role Hypotension
e uce re -ce e orma y
Microvascular thrombosis
Dysfunction of the vascular endothelium
Loss of barrier integrity
Mitochondrial damage
Impairs cellular oxygen
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Treatment
Two bundles of care
Initial management bundle within 6 hours
A management bundle to be accomplished inthe ICU
mitigate the immediate threats ofuncontrolled infection.
Intravenous fluids, vasopressors, oxygentherapy and mechanical ventilation pro-vided as necessary
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Search for new therapy
During the past 30 years
Failure to convert biologic features of sepsis
into effective new therapiesInterrupt the initial cytokine cascade (e.g.,
-
inflammatory cytokine strategies)
Interfere with dysregulated coagulation
(e.g., antithrombin or activated protein C).
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Search for new therapy
Activated protein C
Repeat study, which did not show a benefit Withdraw the drug from the market.
C oFab a ol clonal an i mor necrosis
factor antibody Was halt
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Search for new therapy
Broader immunomodulatory effects,
Glucocorticoids
Intravenous immune globulin, potential benefitbut important questions remain, and its use is
not art of routine ractice
Statin large number observational studies ->
improves the outcome of sepsis and severe
infection
Not been confirmed in randomized, controlledtrials
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Problem of development of strategies
Preclinical studies -> young, healthy miceor rats
often elderly or have serious coexistingillnesses
despite the use of antibiotics, resuscitation,and intensive life support, and the disease
mechanisms in such cases are probablyvery different animal models
Species genetic differences in the
inflammatory host response
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Problem of development of strategies
Enrollment criteria -> very broad
Primary end point -> death from any cause
Little information about mechanism
Does not select patients who are most likely to
benefit Cannot adjust therapy on the basis of the
evolving host response and clinical course
Does not capture potentially important effectson nonfatal outcomes.
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New strategies
More targeted drug development
Incorporate better patient selection, drug
delivery, and outcomeMore genetically diverse, are older, or
ave preex s ng sease.
Longer experiments with more advancedsupportive care
better mimicry of the later stages of sepsis andmultiorgan
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New strategies
Interleukin-7, granulocytemacrophagecolony- stimulating factor, or interferon-
Monocyte HLA-DR expression.Accelerated neurocognitive decline in
surv vors o seps s ec an sm
Biomarkers such as whole-genomeexpression patterns in peripheral-blood
leukocytes may aid in stratifying patients into more
homogeneous subgroups or in developing
more targeted therapeutic interventions.
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