Severe Sepsis NEJM 2013 Ppt2

7/26/2019 Severe Sepsis NEJM 2013 Ppt2

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Review Article: Critical Care Medicine

Severe Sepsis and Septic Shock

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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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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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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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Severe Sepsis NEJM 2013 Ppt2

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