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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Clinical Manifestations.
Hypotension
Cold and clammy skin
Mottling
Tachycardia Cold shock
Cyanosis
Narrow pulse pressure Hypoxemia
Acidosis.
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Clinical Manifestations.
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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Antibiotic Therapy (2008)
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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Antibiotic Therapy (2008)
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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Source identification and control
(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)
Source identification and control
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Source identification and control
(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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Fluid Therapy (2008)
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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Fluid Therapy (2008)
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
Blood Product Administration
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Blood Product Administration
(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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Blood Product Administration (2008)
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)
Blood Product Administration (2008)
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Blood Product Administration (2008)
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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Thanks for your attention
Avoid Sepsis