Sepsis septic shock the lect

8/7/2019 Sepsis septic shock the lect

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SepsisSeptic shock

Hamed Rashad


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Mortality from SepsisMartinNEJM 2003


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Reference Diseases

Incidence in US (cases per 100,000)

AIDS1 17

Colon and rectal cancer2 48

Breast cancer2 112

Congestive heart failure3 ~196

Severe sepsis4 ~300

Number of deaths in US each year

Acute myocardial infarction5 218,000

Severe sepsis4 215,000

1Centers for Disease Control and Prevention. 2000. Incidence rate for 1999.2American Cancer Society. 2001. Incidence rate for 1993-1997.4

Angus DC et al. 2001. Crit Care Med 29:1303-1310.5National Center for Health Statistics. 2001.


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Sepsis on the Rise

Incidence projected to rise during the next decade Aging population especially in developed nations

Increased awareness and diagnosis Immunocompromised patients e.g. cancer

therapy, transplantation)

Invasive procedures (ventilators, catheters, prostheses)

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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Systemic Inflammatory

Response Syndrome Systemic Inflammatory Response Syndrome

(SIRS)--the beginning of illness

2 of the following: Temp > 38C or < 36C

Heart rate > 90 pm

Respiratory rate > 20 pm WBC > 12,000, < 4,000 or bands > 10%

Bone, et al. 1992. Chest 101:1644-1655


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Sepsis

Sepsis

SIRS + infection

Severe sepsis Sepsis with organ dysfunction, hypoperfusion or

hypotension

Septic Shock

Sepsis with hypotension and perfusion abnormalities

despite adequate volume replacement

Bone, et al. 1992. Chest 101:1644-1655


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Definition

Bone et al. Chest. 1992;101:1644;

Wheeler and Bernard. N Engl J Med.1999;340:207.

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma

SevereSevereSepsisSepsis

Sepsis with 1 sign of organ failureSepsis with 1 sign of organ failure Cardiovascular (refractoryCardiovascular (refractory

hypotension)hypotension) RenalRenal RespiratoryRespiratory

HepaticHepatic HematologicHematologic CNSCNS Unexplained metabolic acidosisUnexplained metabolic acidosis

ShockShock


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Multiple Organ Dysfunction

Syndrome (MODS/MOF)MODS/MOF = the presence of altered organ

function in an acutely ill patient such thathomeostasis cannot be maintained without

intervention. Primary MODS = a well-defined insult, occurs early andcan be directly attributable to the insult itself (eg, renalfailure due to rhabdomyolysis).

Secondary MODS = not in direct response to the insultitself, but as a consequence of a host response. MODSrepresents the more severe end of severity of illnesscharacterized by SIRS/sepsis.

Crit Care Med 1992; 20:864


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Identifying Acute Organ

Dysfunction as a Marker of

Severe SepsisTachycardia

Hypotensio

n CVP PAOP

JaundiceEnzymesAlbuminPT

Altered

Consciousn

ess

Confusion

Psychosis

Tachypnea

PaO2


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Septic Shock

Septic shock = sepsis induced hypotensiondespite adequate fluid resuscitation along withperfusion abnormalities that may include, but arenot limited to :

lactic acidosis, oliguria, or

an acute alteration in mental status.

Hypotension = systolic BP of


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Septic shock :Causes

--Common sites of infection in decreasing order :

the chest, the abdomen, and the genitourinary

tract.

70% due to gram-negative bacteria

(Enterobacteriaceae, P aeruginosa)

30% are caused by gram-positive bacteria (Streptpneumoniae, Staph aureus, Enterococ species).


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Primary Sites of Infection in a recent large

study of Septic shock

Percentof

Pa

tients

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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Changes in the Documented Causes ofSepsisMartin NEJM 2003


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Homeostasis Is Unbalanced in

Severe Sepsis

Carvalho AC, Freeman NJ. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock.1996;5:223-8; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44.


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Why do people die from Sepsis?

Very few organisms produce toxins that cause death directly

Diptheria

Tetanus, botulism

Pseudomonas aeruginosa ?

Death from sepsis is mainly due toinflammation


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Pathogenesis of Sepsis

A wide variety of microorganisms cause sepsis How--there must be some common

mechanism

Interaction of specific Pathogen Associated MolecularPatterns (PAMPs)with Toll-like receptors (Tlrs) onthe macrophage stimulate production of inflammatory

mediators


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Innate Immune response Sepsis Interaction of a microbial signature with a toll-like receptor leads to activation of

innate immune mechanism

Antimicrobial peptide (DEFENSINS) synthesis and release which can kill

most organisms

Release of Mediators of inflammation - cytokines, chemokines

PMN leucocytes come into the site of inflammation to

phagocytize organisms--release enzymes

Normally protective but either overwhelmed by bacterialinocula or some type of dysregulation leads to severe SEPSIS


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Synthesis and release of Effector molecules

leading to the SEPSIS syndrome and shock


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Crit Care Med 2000 28(4):N3-N12


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Cytokine Storm ?

High viral load

Genetic predisposition

to immune hyperstimulation

Good sideremove virus

Bad side

ARDS

MODS

CorticosteroidIncomplete Rx

or relapse ???


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Pathophysiology

What type of shock is septic shock?

Septic shock has features of :

Hypovolemic shock

Cardiac shock

Distributive shock.


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Pathophysiology ofseptic shock

and SIRS The hemodynamic derangements observed

in septic shock and SIRS are due to a

complicated cascade of inflammatorymediators released in response to infection,

inflammation, or tissue injury.


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Pathophysiology ofsepticshock

and SIRS Tumor necrosis factor-alpha (TNF-alpha),

interleukin (IL)-1b, and IL-6 act

synergistically with other cytokines andphospholipid-derived mediators to produce

the complex alterations in vascular and

myocardial function, which leads tomaldistribution of blood flow


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Pathophysiology:

Decreased tissue perfusion results primarily

from :

1-arterial hypotension due to reduction inSVR.

2-reduction in effective circulatingplasma

volume due to: a-- decrease in venous toneand subsequent pooling of blood in venous

capacitance vessels.


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Pathophysiology:

b-loss of intravascular volume into the interstitium

due to increased capillary permeability also

occurs. Finally, primary myocardial dysfunction often is

present as manifested by ventricular dilatation,

decreased ejection fraction (despite normal stroke

volume and cardiac output), and depressedventricular function curves


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InfectionInfection

Microbial ProductsMicrobial Products(exotoxin/endotoxin)(exotoxin/endotoxin)

Cellular ResponsesCellular Responses

OxidasesOxidasesPlateletPlateletActivationActivation KininsKininsComplementComplement

Coagulopathy/DICCoagulopathy/DICVascular/Organ System InjuryVascular/Organ System Injury

Multi-Organ FailureMulti-Organ Failure

DeathDeath

EndothelialEndothelialdamagedamage Endoth

elialdamage

Endothelialdama

ge

CoagulationCoagulationActivationActivation

CytokinesCytokinesTNF, IL-1, IL-6TNF, IL-1, IL-6

Pathogenesis of Severe Sepsis


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Severe Sepsis: The Final Common Pathway

Endothelial Dysfunction and

Microvascular Thrombosis

Hypoperfusion/Ischemia

Acute Organ Dysfunction

(Severe Sepsis)

Death

Cytokine storm


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Clinical Manifestations.

The Continuum of infection

to

MODS and Death

(Clinical Definition)


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History:


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Physical examination:

Hypotension - With systolic blood pressure less than 90 mm Hg or areduction of 40 mm Hg from baseline

Fever

Heart rate - Greater than 90

Respiratory rate - Greater than 20

Extremities - Frequently are warm - bounding pulses and increased pulsepressure .


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Septic Shock Is UniqueSeptic Shock Is Unique

Cardiac output may be normal, increased,or decreased.

Hypotension and poor end-organ perfusion may bepresent despite good skin perfusion. Hypotension

is still a sign of decompensation.

Early signs of sepsis/septic shock include Fever or hypothermia

Tachycardia and tachypnea

Leukocytosis, leukopenia, or increased bands


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Septic Shock: Warm Shock

Early, compensated, hyperdynamic state

Clinical signs

Warm extremities with bounding pulses, tachycardia,tachypnea, confusion.

Physiologic parameters

widened pulse pressure, increased cardiac output and mixed

venous saturation, decreased systemic vascular resistance.

Biochemical evidence:

Hypocarbia, elevated lactate, hyperglycemia


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Septic Shock: ColdSeptic Shock: Cold

ShockShock

Late, uncompensated stage with drop in cardiac output.

Clinical signs

Cyanosis, cold and clammy skin, rapid, thready pulses, shallow

respirations. Physiologic parameters

Decreased mixed venous sats, cardiac output and CVP, increased SVR,thrombocytopenia, oliguria, myocardial dysfunction, capillary leak

Biochemical abnormalities

Metabolic acidosis, hypoxia, coagulopathy, hypoglycemia.


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s Cold Shock rapidly progresses toCold Shock rapidly progresses to

MOSF or death, if untreatedMOSF or death, if untreated

s Multi-Organ System Failure: Coma,Multi-Organ System Failure: Coma,ARDS, CHF, Renal Failure, Ileus,ARDS, CHF, Renal Failure, Ileus,

hemorrhage, DIChemorrhage, DIC

s More organ systems involved, worseMore organ systems involved, worse

the prognosisthe prognosis

Septic Shock (cont)


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Clinical Manifestations.Recognition of Septic Shock:

Inflammatory triad- Fever

Tachycardia

flushed skin Warm

Shock Hypoperfusion

Altered sensorium

Urine output

>CFT

Wide pulse pressure.......bounding pulses


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Hypotension

Cold and clammy skin

Mottling

Tachycardia Cold shock

Cyanosis

Narrow pulse pressure Hypoxemia

Acidosis.


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Staging of Septic Shock:

I. Compensated / Preshock / Hyperdynamic

II.Decompensated / Organ hypoperfusion

III. End organ failure / Irreversible


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Lab Studies:

All patients with evidence of shock should have the followingstudies performed: CBC with differential

Arterial blood gas

Serum lactate if metabolic acidosis or elevated anion gap is present

Electrolytes

BUN

Creatinine (CR)

Glucose

Urinalysis

Blood cultures

Urine cultures


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Imaging Studies:

All patients should have a chest x-ray.

Flat and upright abdominal radiographs may be omitted if the abdomen iscompletely benign or if an obvious source of extraabdominal sepsis noted.

In suspected cases of cholecystitis or pancreatitis, abdominal ultrasound ismost useful to assess for cholelithiasis, biliary dilatation, and fluidcollections around the gallbladder or the head of the pancreas.

Consider abdominal CT scan with oral and/or intravenous contrast forother abdominal sources for sepsis


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Other Tests:

ECG should be performed to examine for

evidence of underlying cardiac pathology

(left ventricular hypertrophy, corpulmonale, low voltage, bundle branch

block) or acute changes of ischemia or

pericarditis


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Management

Prevention:

1. Immunisation

2. Prompt treatment of local infections

3. Hospitalized patient: look out for nidus

of infection- IV lines, catheters, E.tubes


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ManagementRecognise septic shock early:

Remember- Inflammatory triad

Signs of hypoperfusion

Do not wait for the BP to fall !

Lower limit for systolic BP in children = 70 +( age

x 2)


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Management.

Two means of death:

1. Shock.

2. Multi organ failure. Aims of treatment:

1. Assure perfusion of critical vascular beds.

( cerebral, coronary, renal)2. Rx underlying cause.


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Guidelines for Management of Severe Sepsis and Septic

Shock I. MANAGEMENT OF

SEVERE SEPSIS Initial Resuscitation Diagnosis

Antibiotics Therapy Source Control Fluid therapy Vasopressors Inotropic Therapy Corticosteroid

Recombinant Human ActivatedProtein C (rhAPC)

Blood Product Administration

II. SUPPORTIVE THERAPYOF SEVERE SEPSIS

Mechanical Ventilation ofSepsis-induced ALI/ARDS

Sedation, Analgesia, and N-MBlockade in Sepsis Glucose Control Renal Replacement Bicarbonate Therapy DVT Prophylaxis

Stress Ulcer Prophylaxis Selective Digestive Tract

Decontamination (SDD) Consideration for Limitation of

Support

III. Pediatric Consideration


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Most Effective therapies

Early recognition of preshock- tachypnealeading to respiratory alkalosis

Low Pco2,pH >7.45 Lots of intravenous Fluids

Antibiotics

Effectiveantibiotics Timely administration of Effective

antibiotics


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Treatment

Nearly all patients with shock should be

admitted to an ICU.

Vital signs and fluid intake and output shouldbe measured and charted on an hourly basis.

Adequate intravenous access should be

obtained.


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Treatment

A central venous access device should be

considered if vasoactive drug support is required. Most patients should have an indwelling urinary

catheter placed.

All patients should be treated prophylactically

against thromboembolic disease, gastric stress

ulceration, and pressure ulcers of the skin.


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Goals of treatment

The 2 primary goals are to :

1- reverse the initiating cause of shock

(e.g.treat infection)

2- stabilize the patient hemodynamical.

The initial resuscitation should be

accomplished within the first hour of treatment.


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Treatment

Oxygen by mask.

In patients with altered mentalstatus,respiratory distress, or severehypotension, elective endotrachealintubation and mechanical ventilationshould be considered strongly.


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Treatment

In all patients with sepsis, Empiric antibiotictherapy should be initiated immediately

Antimicrobial coverage should beBroad


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Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular

management of septic shock. Crit Care Med2003;31:946-955.

Initial ResuscitationInitial Resuscitation


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Early Goal-Directed Therapy

1000 ml of crystalloid or 300-500 ml bolus of colloid q 30

min to keep CVP 8-12 mmHg

Vasoactive agents (MAP: 65 mmHg)

Vasopressors if MAP < 65 mmHg

Vasodilator if MAP > 90 mmHg

Transfusion ( Hct > 30%) and Dobutamine if ScvO2< 70% or

mixed venous < 65%

Keep urine output: 0.5 ml.kg -1.hr-1

In hospital mortality was 30.5% vs. 46.5% in control group

River et al. N Engl J Med, 20

EGDT fi t 6


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EGDT first 6

hours in ER

500ml bolus ofcolloid every 30min

Dobutamin started at

2.5 ug/kg/min,

increase by

2.5ug/kg/min every

30 min, or untilmaximal dose

20ug/kg/min given

Decrease

dobutamin doseif MAP

>65mmHg or

HR> 120bpm


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Initial Resuscitation (2008)Initial resuscitation (first 6 hrs)

Begin resuscitation immediately in patients with hypotension or elevatedserum lactate 4 mmol/L; do not delay pending ICU admission (1C)Resuscitation goals (1C)

CVP 812 mm Hg aMean arterial pressure 65 mm HgUrine output 0.5 mL/kg/hrCentral venous (superior vena cava) oxygen saturation 70% or mixed

venous 65%If venous oxygen saturation target is not achieved (2C)

Consider further fluidTransfuse packed red blood cells if required to hematocrit of 30%

and/orStart dobutamine infusion, maximum 20 g/kg/min


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Diagnosis

Obtain appropriate cultures before starting antibiotics provided this

does not significantly delay antimicrobial administration (1C)

Obtain two or more BCs

One or more BCs should be percutaneous

One BC from each vascular access device in place 48 hrs

Culture other sites as clinically indicated

Perform imaging studies promptly to confirm and sample any source

of infection, if safe to do so (1C), (ex. Sonography suitable, transport

outside unit may be dangerous)


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Role of Infection Control

Right Drugs for Right patients at Right time

De-Escalation Therapy (For severe

infection in ICU) Why

How

Outcomes

Resistance


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Antibiotic Therapy (2008)

Begin intravenous antibiotics as early as possible andalways within the first hour of recognizing severesepsis (1D) and septic shock (1B)

In the presence of septic shock, each hour delay

in achieving administration of effectiveantibiotics is associated with a measurableincrease in mortality

Broad-spectrum: one or more agents active againstlikely bacterial/fungal pathogens and with goodpenetration into presumed source (1B)

Watch out MRSA in some communities and healthcaresettings


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Reassess antimicrobial regimen daily to

optimize efficacy, prevent resistance,

avoid toxicity, and minimize costs (1C)

Consider combination therapy in

Pseudomonas infections (2D)

Consider combination empiric therapyin neutropenic patients (2D)


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Combination therapy 35 days and de-

escalation following susceptibilities (To

single therapy) (2D)

Duration of therapy typically limited to 710

days; longer if response is slow or there are

undrainable foci of infection or immunologic

deficiencies (1D) Stop antimicrobial therapy if cause is found

to be noninfectious (1D)

Optimum therapy of Sepsis and


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p py pShock

Antibiotics remain the most critical choice to be made

TIMELY-reduces mortality EFFECTIVE, BROAD SPECTRUM-reduces mortality

DIFFERENT antibiotics for different patients

P. aeruginosa continues to be associated with highestmortality

Resistance issues need to be kept in mind

A large number of patients with the sepsis syndrome will not have an

organism cultured but should be treated with antibiotics

Prevent the development of septic shock - fluids and

Right antibiotics


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Antibiotic Choices

Given the world wide resistance issues the most effectiveantibiotic choices to cover gram negatives would be

Fourth generation cephalosporins aminoglycoside (Geographic location)

Carbapenems aminoglycoside (Pseudomonasresistance during therapy of Lung infections)

Pip-Tazobactam + an aminoglycoside (Esblresistance)

If the incidence of MRSA is high and gram positive coverage

is needed, add an anti Staphylococcal agent --Vanco,Teicoplanin


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Choosing the RIGHT antibiotic in Sepsis

Site of Infection, if known it helps to limit choices intraabdominal, or necrotizing soft tissue infection needs anaerobic coverage.

Skin infections require gram positive coverage

Lung most common site of documented infection-P.

aeruginosa, S. aureus, Know resistance picture in hospital

ESBLs, P. aeruginosa, choose best drugs against these

Know resistance in community if sepsis is communityacquired - S. aureus, S. pneumoniae, E.coli

Give the antibiotic as soon as possible

Non antibiotic therapy of septic shock


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Non antibiotic therapy of septic shock

2002 opinion

Source identification and control


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(2008)

A specific anatomic site of infection should beestablished as rapidly as possible (1C) and within

first 6 hrs of presentation (1D)

E.g., necrotizing fascitis, diffuse peritonitis, cholangitis,

intestinal infarction) Formally evaluate patient for a focus of infection

amenable to source control measures (e.g. abscess

drainage, tissue debridement, removal of a potentially

infected device, or the definitive control of a source

of ongoing microbial contamination) (1C)



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(2008)

Implement source control measures as soon aspossible following successful initial resuscitation(1C) (exception: infected pancreatic necrosis, wheresurgical intervention is best delayed) (2B)

Choose source control measure with maximumefficacy and minimal physiologic upset (1D) e.g., percutaneous rather than surgical drainage of an

abscess

Remove intravascular access devices if potentiallyinfected (1C) Prompt remove after other vascular access had been

established


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Fluid Therapy (2008)

Fluid resuscitation may consist of natural or artificial

colloids or crystalloids (1B)

:


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Resuscitation initially target a central venous pressure

of 8 mm Hg (12 mm Hg in mechanically ventilated

patients) (1C)

A fluid challenge technique be applied wherein fluidadministration is continued as long as the

hemodynamic improvement (e.g., arterial pressure,

heart rate, urine output) continues (1D)


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The rate of fluid administration be reduced when

cardiac filling pressures (central venous pressure or

pulmonary artery balloon-occluded pressure)

increase without concurrent hemodynamicimprovement

(1D)


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Vasopressors (2008)

Mean arterial pressure (MAP) be maintained 65 mm Hg (65) (1C)

Sustain life and maintain perfusion in the face of life-threatening

hypotension

Either NOREPI or DOPA administered through a centralcatheter is the initial vasopressor of choice (1C)

Epinephrine, phenylephrine, or vasopressin should not be

administered as the initial vasopressor in septic shock (2C).

Vasopressin 0.03 units/min may be subsequently added tonorepinephrine with anticipation of an effect equivalent to

norepinephrine alone


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Vasopressors (2008)

Epinephrine be the first chosen alternative agent in

septic shock that is poorly responsive to

norepinephrine or dopamine (2B)

Do not use low-dose dopamine for renal perfusion(1A)

Bellomo et al. Lancet 2000

In patients requiring vasopressors, place an

arterial catheter as soon as possible.(1D)

Effects of Dopamine NorepinephrineEffects of Dopamine Norepinephrine


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Effects of Dopamine, Norepinephrine,Effects of Dopamine, Norepinephrine,and Epinephrine on the Splanchnicand Epinephrine on the Splanchnic

Circulation in Septic ShockCirculation in Septic Shock

Figure 2, page 1665, reproduced with permission from De Backer D, Creteur J, Silva E, Vincent

JL. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in

septic shock: Which is best? Crit Care Med2003; 31:1659-1667


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Corticosteroid (2008)

Consider intravenous hydrocortisone for adult

septic shock when hypotension responds poorly to

adequate fluid resuscitation and vasopressors (2C)

ACTH stimulation test is not recommended to

identify the subset of adults with septic shock who

should receive hydrocortisone (2B)

Hydrocortisone is preferred to dexamethasone(2B)


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Corticosteroid in Septic Shock High doses of corticosteroids do not improve survival and may

worsen outcomes by increasing the frequency of secondaryinfections

Low-dose (?physiologic?) steroids may be beneficial because

of relative adrenal insufficiency Treat patients who still require vasopressors despite fluid replacementwith hydrocortisone 200-300 mg/day, for 7 days in three or fourdivided doses or by continuous infusion

Bone, et al. NEJM 1987; 317-658Bone, et al. NEJM 1987; 317-658

VA Systemic Sepsis Cooperative Study Group. NEJM 1987; 317:659-665VA Systemic Sepsis Cooperative Study Group. NEJM 1987; 317:659-665


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Hydrocortisone Therapy for

Patients with Septic Shock In the multicenter, randomized, double-blind, placebo-

controlled trial 251 patients: 50 mg hydrocortisone iv q6h for 5 days, the dose was

then tapered during a 6-day period

248 patients iv placebo

28-day mortality, 86/251 (34.3%) in the hydrocortisonegroup vs 78/248 (31.5%) in the placebo group (P=0.51)

In the hydrocortisone group, shock was reversed more

quickly than in the placebo group However, there were more episodes of superinfection,

including new sepsis and septic shock.

Sprung et al. NEJM 358(2): 111, 2008


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Corticosteroid (2008)

Fludrocortisone (50 g orally once a day) may be includedif an alternative to hydrocortisone is being used that lackssignificant mineralocorticoid activity. Fludrocortisone ifoptional if hydrocortisone is used (2C)

Steroid therapy may be weaned once vasopressors are nolonger required (2D)

Hydrocortisone dose should be 300 mg/day (1A)

Do not use corticosteroids to treat sepsis in the absence ofshock unless the patients endocrine or corticosteroidhistory warrants it (1D)


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Figure 2A, page 867, reproduced with permission from Annane D, SFigure 2A, page 867, reproduced with permission from Annane D, Sbille V, Charpentier C,bille V, Charpentier C, etet

al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality inal. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in

patients with septic shock.patients with septic shock. JAMAJAMA 2002; 288:862-8712002; 288:862-871

Steroid Therapy


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Thrombin

Thrombomodulin

ProteinC (Inactive) Protein C Activity

Blood VesselBlood Flow Protein C

Receptor

Protein

S

Human Activated Protein CHuman Activated Protein CEndogenous Regulator of CoagulationEndogenous Regulator of Coagulation


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Human Activated Protein C in Septic

Shock Activated protein C had anti-thrombotic,

anti-inflammatory and pro-fibrinolytic

properties Drotrecogin Alfa is the first anti-inflammatory

agent that proved effective in the treatment of

sepsis

From Recombinant human activatedprotein c worldwide evaluation in severe

sepsis (PROWESS) study group

Bernard et al. NEJM, 2001


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35

30

25

20

15

10

5

0

30.8%

24.7%

Placebo

(n-840)

Drotrecog

in alfa(activated

) (n=850)

Mor t alit y

( %)

6.1%

absolutereduction

in mortality

Results: 28-Day All-Cause MortalityPrimary analysis

results

2-sided p-value 0.005

Adjusted relative risk reduction 19.4%

Increase in odds of survival 38.1%

Adapted from Table 4, page 704, with permission from Bernard GR, Vincent JL, Laterre PF, et al.

Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med

2001; 344:699-709


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Mortality and APACHE II QuartileMortality and APACHE II Quartile

APACHE II Quartile

*Numbers above bars indicate total

deaths

0

5

10

15

20

25

30

35

40

45

50

1st (3-19) 2nd (20-24) 3rd (25-29) 4th (30-53)

Placebo

Drotrecogin

Mo

rta

lit y

(

p e

rc

e n

t)

26:3357:49

58:48

118:80

Adapted from Figure 2, page S90, with permission from Bernard GR. Drotrecogin alfa (activated)

(recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med2003;

31[Suppl.]:S85-S90


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Mortality and Numbers of Organs FailingMortality and Numbers of Organs Failing

Percent

Mortality

0

10

20

30

40

50

60

1 2 3 4 5

Placebo

Drotrecogin

Number of Organs Failing at Entry

Adapted from Figure 4, page S91, with permission from Bernard GR. Drotrecogin alfa (activated)

(recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med2003;

31[Suppl.]:S85-S90

Contraindications to Use of Recombinant

H A ti t d P t i C ( hAPC)


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Human Activated Protein C (rhAPC)

Active internal bleeding

Recent (within 3 months) hemorrhagic stroke

Recent (within 2 months) intracranial or intraspinal

surgery, or severe head trauma Trauma with an increased risk of life threatening

bleeding

Presence of an epidural catheter

Intracranial neoplasm or mass lesion or evidence ofcerebral herniation

Known hypersensitivity to rhAPC or any componentof the product



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(2008) Red Blood Cells

Give red blood cells when hemoglobin

decreases to 7.0 g/dL (70 g/L) to target ahemoglobin of 7.09.0 g/dL in adults (1B).

A higher hemoglobin level may be required in

special circumstances (e.g., myocardial ischaemia,

severe hypoxemia, acute hemorrhage, cyanotic heart

disease, or lactic acidosis)

Blood Product Administration (2008)


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Do not use erythropoietin to treat sepsis-related anemia.Erythropoietin may be used for other accepted reasons

(chronic renal failure). (1B)

Do not use fresh frozen plasma to correct laboratory

clotting abnormalities unless there is bleeding orplanned invasive procedures (2D)

Do not use antithrombin therapy (1B)



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Administer platelets when (2D)

Counts are 5000/mm3 (5x 109/L) regardless of bleeding

Counts are 500030,000/mm3 (530x109/L) and there is

significant bleeding risk

Higher platelet counts (50,000/mm3 [50x 109/L]) are

required for surgery or invasive procedures


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Mechanical Ventilation of Sepsis-Induced ALI/ARDS(2008)

Mechanical Ventilation of


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Sepsis-Induced ALI/ARDS

Target a tidal volume of 6 mL/kg (predicted) bodyweight in patients with ALI/ARDS (1B)

Target an initial upper limit plateau pressure 30 cm

H2O. Consider chest wall compliance when

assessing plateau pressure (1C)

If plateau pressure remain > 30 after reduction of

tidal volume to 6 ml/kg PBW, tidal volume should

be reduced further to as low as 4 ml/kg

M h i l t


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Mechanical vent

Allow PaCO2 to increase above normal, if needed, tominimize plateau pressures and tidal volumes (1C)

Permissive hypercapnia

Be limited in patients with preexisting metabolic acidosis and

contraindicated in patients with increased initracranial pressure. Set PEEP to avoid extensive lung collapse at end-expiration

(1C)

Titrate PEEP based on

1. Bedside measurement of thoracopulmonary compliance

2. Guided by the FiO2 required to maintain adequate oxygenation

PEEP > 5 cm H20 to avoid lung collapse


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0

5

10

15

20

25

30

35

40

6 ml/kg

12 ml/kg

%

Mo

rtality

ARDSnet Mechanical Ventilation Protocol

Results: Mortality

Adapted from Figure 1, page 1306, with permission from The Acute Respiratory Distress

Syndrome Network. N Engl J Med 2000;342:1301-1378


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The Role of Prone Positioning in ARDSThe Role of Prone Positioning in ARDS

70% of prone patients70% of prone patients

improved oxygenationimproved oxygenation

70% of response70% of response

within 1 hourwithin 1 hour 10-day mortality rate in10-day mortality rate in

quartile with lowestquartile with lowest

PaO2:FIO2 ratio (PaO2:FIO2 ratio ( 88)88) ProneProne 23.1%23.1%

SupineSupine 47.2%47.2%

Gattinoni L, et al. N Engl J Med2001;345:568-73; Slutsky AS. N Engl J Med2001;345:610-2.

Kaplan-Meierestimates ofsurvival at 6

months

Surviv

al

(%)10

07550250

30

60

90 120

150

180

0Days

Supine

groupPronegroupP=0.65


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Mechanical Ventilationof Severe Sepsis

Maintain mechanically ventilated patients in asemirecumbent position (head of the bed raised to 45)

unless contraindicated (to limit aspiration risk and to

prevent the development of VAP) (1B), between 30 and

45 (2C)

Drakulovic et al. Lancet 1999; 354:1851-1858


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Sedation and Analgesia in Sepsis(2008)

Use sedation protocols with a sedation goal for critically ill

mechanically ventilated patients Ramsay score: daytime: 2-3, night time: 4-5 Use either intermittent bolus sedation or continuous

infusion sedation to predetermined end points (sedationscales), with daily interruption/ lightening to produce

awakening. Re-titrate if necessary (1B)Kollef, et al. Chest 1998; 114:541-548

Brook, et al. CCM 1999; 27:2609-2615

Kress, et al. NEJM 2000; 342:1471-1477


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Neuromuscular Blockers

Avoid neuromuscular blockers where possible

Risk of prolonged neuromuscular blockade following

discontinuation

Monitor depth of block with train-of-four whenusing continuous infusions (1B)


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Glucose Control

After initial stabilization

Glcose be maintained


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Renal Replacement

Absence of hemodynamic instability Intermittent hemodialysis and continuous venovenous

filtration equal (CVVH)

Hemodynamic instability CVVH preferred --- to facilitate management

of fluid balance in septic patients, no improved inregional perfusion and survival benefit

Grade 2B

Grade 2D

2008 update


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Bicarbonate therapy not recommended toimprove hemodynamics in patients withhypoperfusion-induced lactic acidemia pH>7.15

Will increase Na, fluid overload,increase lactate and PCO2

Grade 1B

Cooper, et al. Ann Intern Med 1990; 112:492-498

Mathieu, et al. CCM 1991; 19:1352-1356

Bicarbonate Therapy


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Deep Vein Thrombosis Prophylaxis

Heparin (either UFH 2-3times perday or LMWH

once daily) was recommended in patients with

severe sepsis unless contraindications (1A)

If contraindication for heparin, use mechanical

prophylactic device (1A)

Mechanical device (unless contraindicated)such as graduated compression stockings or

intermittent compression devices


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Stress Ulcer prophylaxis

H2 blocker

Proton pump inhibitor

The benefit of prevention of upper GI bleed must

be weighed against the potential effect of an

increased stomach pH on development of

ventilator-associated pneumonia

2008 update

Grade 1A

Grade 1B

Intensive Care Med2006;32:1151-1158

Monitoring a Child With Septic


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Monitoring a Child With Septic

Shock. Frequent monitoring is

MOST IMPORTANT to recognise and Rx

complications.1. Pulse 5. Urine output.

2. BP6. ABG

3. Level of

consciousness 7. PT/PTT/PC

4. 02 saturation 8. CVP

Management summary


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Management- summary.

Five important points1. ABC, supplement 02 always.

2. IV or IO access and fluid resuscitation upto

60 mL/Kg.3. Early dopamine infusion @10g/Kg/min

4. Empirical antibiotic.

5. Frequent monitoring.

Summary: gain in mortality in


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Summary: gain in mortality in

sepsis Activated protein C 31% vs 25% (-6%) Bernard et al. NEJM 2001; 344: 699-709

Early goal 47% vs 30% (-17%)

River et al. NEJM 2001; 345: 1368-73

Hydrocortisone 63% vs 53% (-10%)

Annane et al. JAMA 2002; 288: 862-871

Adequate antibiotics therapy 63% vs 31% (-32%)

Valles J et al. Chest 2003; 123: 1615-1624


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A clinician, armed with the sepsis bundles, attacks the three heads of severe sepsis:

hypotension, hypoperfusion and organ dysfunction. Crit Care Med2004; 320(Suppl):S595-

S597


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