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Septic shock

Hamed Rashad
Septic Shock
• Septic shock- once a uniformly fatal
condition with 100% mortality.

• Present recovery rates are more than 50%.

Mortality from Sepsis Martin
NEJM 2003
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
Centers for Disease Control and Prevention. 2000. Incidence rate for 1999.
American Cancer Society. 2001. Incidence rate for 1993-1997.
Angus DC et al. 2001. Crit Care Med 29:1303-1310.
National Center for Health Statistics. 2001.
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

SIRS Sepsi Severe Septic

Infection s Sepsis Shock
Systemic Inflammatory
Response Syndrome
• Systemic Inflammatory Response Syndrome
(SIRS)--the beginning of illness
≥ 2 of the following:
• Temp > 38°C or < 36°C
• Heart rate > 90 pm
• Respiratory rate > 20 pm
• WBC > 12,000, < 4,000 or bands > 10%
Bone, et al. 1992. Chest 101:1644-1655
• Sepsis
– SIRS + infection
• Severe sepsis
– Sepsis with organ dysfunction, hypoperfusion or
• Septic Shock
– Sepsis with hypotension and perfusion abnormalities
despite adequate volume replacement

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

Infection/ Sepsis Severe
Trauma SIRS
Sepsis with ≥1 sign of organ failure
 Cardiovascular (refractory
 Renal
 Respiratory
 Hepatic
Bone et al. Chest. 1992;101:1644;  Hematologic
Wheeler and Bernard. N Engl J Med.  CNS
 Unexplained metabolic acidosis
Multiple Organ Dysfunction
Syndrome (MODS/MOF)
MODS/MOF = the presence of altered organ
function in an acutely ill patient such that
homeostasis cannot be maintained without
 Primary MODS = a well-defined insult, occurs early and
can be directly attributable to the insult itself (eg, renal
failure due to rhabdomyolysis).
 Secondary MODS = not in direct response to the insult
itself, but as a consequence of a host response. MODS
represents the more severe end of severity of illness
characterized by SIRS/sepsis.

Crit Care Med 1992; 20:864

Identifying Acute Organ
Dysfunction as a Marker of
AlteredSevere Sepsis
Consciousn Tachycardia
ess Hypotensio
Confusion n
Psychosis ↑ CVP
PaO2 <70 mm Oliguria
Hg Anuria
SaO2 <90% ↑ Creatinine
PaO2/FiO2 ≤ 300

↓ Platelets
Jaundice ↑ PT/APTT
↑ Enzymes ↓ Protein C
↓ Albumin ↑ D-dimer
↑ PT
Septic Shock
Septic shock = sepsis induced hypotension
despite adequate fluid resuscitation along with
perfusion abnormalities that may include, but are
not limited to :
 lactic acidosis,
 oliguria, or
an acute alteration in mental status.
– Hypotension = systolic BP of <90 mmHg or a reduction
of ≧40 mmHg from baseline in the absence of other
causes for the fall in blood pressure.

Crit Care Med 1992; 20:864

Septic shock :Causes

--Common sites of infection in decreasing order :

the chest, the abdomen, and the genitourinary

– 70% due to gram-negative bacteria

(Enterobacteriaceae, P aeruginosa)
– 30% are caused by gram-positive bacteria (Strept
pneumoniae, Staph aureus, Enterococ species).
Primary Sites of Infection in a recent large
study of Septic shock
60 Drotrecogin Alfa
(activated) N=850
Percent of Patients

Placebo N=840




Lung Intra- Urinary Blood Skin Other
Abdominal Tract

Site of Infection
Changes in the Documented Causes of
Martin NEJM 2003
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.
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 to

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

• Interaction of specific Pathogen Associated Molecular

Patterns (PAMPs)with Toll-like receptors (Tlrs) on
the macrophage stimulate production of inflammatory
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 bacterial

inocula or some type of dysregulation leads to severe SEPSIS
Synthesis and release of Effector molecules
leading to the SEPSIS syndrome and shock
Crit Care Med 2000 28(4):N3-N12
Incomplete Rx
Corticosteroid or relapse ???

High viral load Good side

remove virus

Cytokine Storm ?

Bad side
Genetic predisposition ARDS
to immune hyperstimulation MODS
• What ‘type of shock’ is septic shock?
Septic shock has features of :
– Hypovolemic shock
– Cardiac shock
– Distributive shock.
Pathophysiology of septic shock
and SIRS
• The hemodynamic derangements observed
in septic shock and SIRS are due to a
complicated cascade of inflammatory
mediators released in response to infection,
inflammation, or tissue injury.
Pathophysiology of septic shock
and SIRS
• Tumor necrosis factor-alpha (TNF-alpha),
interleukin (IL)-1b, and IL-6 act
synergistically with other cytokines and
phospholipid-derived mediators to produce
the complex alterations in vascular and
myocardial function, which leads to
maldistribution of blood flow
• Decreased tissue perfusion results primarily
from :
• 1-arterial hypotension due to reduction in
• 2-reduction in effective circulating plasma
volume due to: a-- decrease in venous tone
and subsequent pooling of blood in venous
capacitance vessels.
b-loss of intravascular volume into the interstitium
due to increased capillary permeability also
• Finally, primary myocardial dysfunction often is
present as manifested by ventricular dilatation,
decreased ejection fraction (despite normal stroke
volume and cardiac output), and depressed
ventricular function curves
Pathogenesis of Severe Sepsis

Microbial Products

Cellular Responses

Platelet Coagulation Kinins Cytokines

Activation Activation Oxidases Complement TNF, IL-1, IL-6

Vascular/Organ System Injury

Endothelial d he li a l da mage
amage Endot
Multi-Organ Failure

Severe Sepsis: The Final Common Pathway
Cytokine storm
Endothelial Dysfunction and
Microvascular Thrombosis


Acute Organ Dysfunction

(Severe Sepsis)

Clinical Manifestations.
• The Continuum of infection
MODS and Death
(Clinical Definition)
Physical examination:

– Hypotension - With systolic blood pressure less than 90 mm Hg or a

reduction 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 pulse

pressure .
Septic Shock Is Unique
• Cardiac output may be normal, increased,
or decreased.
• Hypotension and poor end-organ perfusion may be
present 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
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
Septic Shock: “Cold
• Late, uncompensated stage with drop in cardiac output.
• Clinical signs
– Cyanosis, cold and clammy skin, rapid, thready pulses, shallow
• 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.
Septic Shock (con’t)
■ Cold Shock rapidly progresses to
MOSF or death, if untreated

■ Multi-Organ System Failure: Coma,

ARDS, CHF, Renal Failure, Ileus,
hemorrhage, DIC

■ More organ systems involved, worse

the prognosis
Clinical Manifestations.
Recognition of Septic Shock:
• Inflammatory triad-
– Fever
– Tachycardia
– flushed skin Warm
• Hypoperfusion
– Altered sensorium
– Urine output
– >CFT
– Wide pulse pressure.......bounding pulses
Clinical Manifestations.
• Hypotension
– Cold and clammy skin
– Mottling
– Tachycardia Cold shock
– Cyanosis
– Narrow pulse pressure
– Hypoxemia
– Acidosis.
Clinical Manifestations.
Staging of Septic Shock:
I. Compensated / Preshock / Hyperdynamic

II.Decompensated / Organ hypoperfusion

III. End organ failure / Irreversible

Lab Studies:

• All patients with evidence of shock should have the following

studies performed:
– CBC with differential
– Arterial blood gas
– Serum lactate if metabolic acidosis or elevated anion gap is present
– Electrolytes
– Creatinine (CR)
– Glucose
– Urinalysis
– Blood cultures
– Urine cultures
Imaging Studies:
• All patients should have a chest x-ray.

• Flat and upright abdominal radiographs may be omitted if the abdomen is

completely benign or if an obvious source of extraabdominal sepsis noted.

• In suspected cases of cholecystitis or pancreatitis, abdominal ultrasound is

most useful to assess for cholelithiasis, biliary dilatation, and fluid
collections around the gallbladder or the head of the pancreas.

• Consider abdominal CT scan with oral and/or intravenous contrast for

other abdominal sources for sepsis
Other Tests:
• ECG should be performed to examine for
evidence of underlying cardiac pathology
(left ventricular hypertrophy, cor
pulmonale, low voltage, bundle branch
block) or acute changes of ischemia or
1. Immunisation

2. Prompt treatment of local infections

3. Hospitalized patient: look out for nidus

of infection- IV lines, catheters, E.tubes
Recognise 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)
• 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.
Guidelines for Management of Severe Sepsis and Septic
– Initial Resuscitation – Mechanical Ventilation of
– Diagnosis Sepsis-induced ALI/ARDS
– Antibiotics Therapy – Sedation, Analgesia, and N-M
– Blockade in Sepsis
Source Control
– – Glucose Control
Fluid therapy
– Renal Replacement
– Vasopressors
– – Bicarbonate Therapy
Inotropic Therapy
– DVT Prophylaxis
– Corticosteroid
– Stress Ulcer Prophylaxis
– Recombinant Human Activated
Protein C (rhAPC) – Selective Digestive Tract
– Blood Product Administration Decontamination (SDD)
– Consideration for Limitation of
• III. Pediatric Consideration
Most Effective therapies
• Early recognition of preshock- tachypnea
leading to respiratory alkalosis
– Low Pco2, pH >7.45
• Lots of intravenous Fluids
• Antibiotics
• Effective antibiotics
• Timely administration of Effective
• Nearly all patients with shock should be
admitted to an ICU.
• Vital signs and fluid intake and output should
be measured and charted on an hourly basis.
• Adequate intravenous access should be

• 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.
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.
• Oxygen by mask.

• In patients with altered mental

status,respiratory distress, or severe
hypotension, elective endotracheal
intubation and mechanical ventilation
should be considered strongly.
• In all patients with sepsis, Empiric antibiotic
therapy should be initiated immediately

• Antimicrobial coverage should be Broad

Initial Resuscitation

Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular
management of septic shock. Crit Care Med 2003;31:946-955.
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

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

River et al. N Engl J Med, 200

EGDT first 6
hours in ER
500ml bolus of
colloid every 30min
Dobutamin started at
2.5 ug/kg/min,
increase by
2.5ug/kg/min every
30 min, or until
maximal dose
20ug/kg/min given

dobutamin dose
if MAP
>65mmHg or
HR> 120bpm
Initial Resuscitation (2008)
Initial resuscitation (first 6 hrs)
 Begin resuscitation immediately in patients with hypotension or elevated
serum lactate 4 mmol/L; do not delay pending ICU admission (1C)
Resuscitation goals (1C)
CVP 8–12 mm Hg a
Mean arterial pressure 65 mm Hg
Urine output 0.5 mL/kg/hr
Central venous (superior vena cava) oxygen saturation 70% or mixed
venous 65%
If venous oxygen saturation target is not achieved (2C)
Consider further fluid
Transfuse packed red blood cells if required to hematocrit of 30%
Start dobutamine infusion, maximum 20 μg/kg/min
• 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)
Role of Infection Control
• Right Drugs for Right patients at Right time
• De-Escalation Therapy (For severe
infection in ICU)
– Why
– How
– Outcomes
• Resistance
Antibiotic Therapy (2008)
• Begin intravenous antibiotics as early as possible and
always within the first hour of recognizing severe
sepsis (1D) and septic shock (1B)
– In the presence of septic shock, each hour delay
in achieving administration of effective
antibiotics is associated with a measurable
increase in mortality
• Broad-spectrum: one or more agents active against
likely bacterial/fungal pathogens and with good
penetration into presumed source (1B)
– Watch out MRSA in some communities and healthcare
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 therapy
in neutropenic patients (2D)
Antibiotic Therapy (2008)
• Combination therapy 3–5 days and de-
escalation following susceptibilities (To
single therapy) (2D)
• Duration of therapy typically limited to 7–10
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
• 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 highest
– 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
Antibiotic Choices
• Given the world wide resistance issues the most effective
antibiotic choices to cover gram negatives would be
– Fourth generation cephalosporins ±
aminoglycoside (Geographic location)
– Carbapenems ± aminoglycoside (Pseudomonas
resistance during therapy of Lung infections)
– Pip-Tazobactam + an aminoglycoside (Esbl
• If the incidence of MRSA is high and gram positive coverage
is needed, add an anti Staphylococcal agent --Vanco,
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 community
acquired - S. aureus, S. pneumoniae, E.coli
• Give the antibiotic as soon as possible
Non antibiotic therapy of septic shock

2002 opinion
Source identification and control
• A specific anatomic site of infection should be
established 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
• Implement source control measures as soon as
possible following successful initial resuscitation
(1C) (exception: infected pancreatic necrosis, where
surgical intervention is best delayed) (2B)
• Choose source control measure with maximum
efficacy and minimal physiologic upset (1D)
– e.g., percutaneous rather than surgical drainage of an
• Remove intravascular access devices if potentially
infected (1C)
– Prompt remove after other vascular access had been
Fluid Therapy (2008)

• Fluid resuscitation may consist of natural or artificial

colloids or crystalloids (1B)
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 fluid
administration is continued as long as the
hemodynamic improvement (e.g., arterial pressure,
heart rate, urine output) continues (1D)
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 hemodynamic
• (1D)
Vasopressors (2008)
• Mean arterial pressure (MAP) be maintained 65 mm Hg (≧
65) (1C)
– Sustain life and maintain perfusion in the face of life-threatening
• Either NOREPI or DOPA administered through a central
catheter 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 to
norepinephrine with anticipation of an effect equivalent to
norepinephrine alone
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
– Bellomo et al. Lancet 2000
• In patients requiring vasopressors, place an
arterial catheter as soon as possible.(1D)
Effects of Dopamine, Norepinephrine,
and Epinephrine on the Splanchnic
Circulation 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 Med 2003; 31:1659-1667
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
Corticosteroid in Septic Shock
• High doses of corticosteroids do not improve survival and may
worsen outcomes by increasing the frequency of secondary
• Low-dose (?physiologic?) steroids may be beneficial because
of relative adrenal insufficiency
– Treat patients who still require vasopressors despite fluid replacement
with hydrocortisone 200-300 mg/day, for 7 days in three or four
divided doses or by continuous infusion

Bone, et al. NEJM 1987; 317-658

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

Corticosteroid (2008)
• Fludrocortisone (50 g orally once a day) may be included
if an alternative to hydrocortisone is being used that lacks
significant mineralocorticoid activity. Fludrocortisone if
optional if hydrocortisone is used (2C)
• Steroid therapy may be weaned once vasopressors are no
longer required (2D)
• Hydrocortisone dose should be 300 mg/day (1A)
• Do not use corticosteroids to treat sepsis in the absence of
shock unless the patient’s endocrine or corticosteroid
history warrants it (1D)
Steroid Therapy

Figure 2A, page 867, reproduced with permission from Annane D, Sébille V, Charpentier C, et
al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in
patients with septic shock. JAMA 2002; 288:862-871
Human Activated Protein C
Endogenous Regulator of Coagulation

Protein Protein C Activity

C (Inactive)
Blood Vessel
Blood Flow ⇒
Thrombin Protein C
Human Activated Protein C in Septic
• Activated protein C had anti-thrombotic,
anti-inflammatory and pro-fibrinolytic
– Drotrecogin Alfa is the first anti-inflammatory
agent that proved effective in the treatment of
From Recombinant human activated
protein c worldwide evaluation in severe
sepsis (PROWESS) study group
Bernard et al. NEJM, 2001
Results: 28-Day All-Cause Mortality
Primary analysis
2-sided p-value 0.005
Adjusted relative risk reduction
Increase in30.8%
odds of survival 38.1%
30 6.1%
24.7% absolute
Mortality (%)

in mortality
15 Placebo Drotrecog
10 in alfa
) (n=850)
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
Mortality and APACHE II Quartile

Mortality (percent)

35 58:48
25 57:49
1st (3-19) 2nd (20-24) 3rd (25-29) 4th (30-53)

APACHE II Quartile
*Numbers above bars indicate total
Adapted from Figure 2, page S90, with permission from Bernard GR. Drotrecogin alfa (activated)
(recombinant human activated protein C) fordeaths
the treatment of severe sepsis. Crit Care Med 2003;
Mortality and Numbers of Organs Failing

Placebo 10
1 2 3 4 5
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 Med 2003;
Contraindications to Use of Recombinant
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
• Presence of an epidural catheter
• Intracranial neoplasm or mass lesion or evidence of
cerebral herniation
• Known hypersensitivity to rhAPC or any component
of the product
Blood Product Administration
(2008) Red Blood Cells

• Give red blood cells when hemoglobin

decreases to 7.0 g/dL (70 g/L) to target a
hemoglobin of 7.0–9.0 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)

• 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 or
planned invasive procedures (2D)
• Do not use antithrombin therapy (1B)
Blood Product Administration (2008)

• Administer platelets when (2D)

– Counts are 5000/mm3 (5x 109/L) regardless of bleeding
– Counts are 5000–30,000/mm3 (5–30x109/L) and there is
significant bleeding risk
• Higher platelet counts (50,000/mm3 [50x 109/L]) are
required for surgery or invasive procedures
Mechanical Ventilation of Sepsis-
Induced ALI/ARDS (2008)
Mechanical Ventilation of
Sepsis-Induced ALI/ARDS
• Target a tidal volume of 6 mL/kg (predicted) body
weight 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
Mechanical vent
• Allow PaCO2 to increase above normal, if needed, to
minimize 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
– 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
ARDSnet Mechanical Ventilation Protocol
Results: Mortality
% Mortality

6 ml/kg
12 ml/kg

Adapted from Figure 1, page 1306, with permission from The Acute Respiratory Distress
Syndrome Network. N Engl J Med 2000;342:1301-1378
The Role of Prone Positioning in ARDS
 70% of prone patients

Survival (%)
improved oxygenation
 70% of response
5 Supine
within 1 hour 5
 10-day mortality rate in 0
2 Prone
quartile with lowest 5 group
PaO2:FIO2 ratio (≤ 88) 0
0 3 6 90 12 15 18
0 Days0 0 0
 Prone — 23.1%
 Supine – 47.2%
estimates of
Gattinoni L, et al. N Engl J Med 2001;345:568-73; Slutsky AS. at 6
N Engl J Med 2001;345:610-2.
Mechanical Ventilation
of Severe Sepsis
• Maintain mechanically ventilated patients in a
semirecumbent 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

Sedation and Analgesia in Sepsis
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 (sedation
scales), 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
Neuromuscular Blockers

• Avoid neuromuscular blockers where possible

– Risk of prolonged neuromuscular blockade following
• Monitor depth of block with train-of-four when
using continuous infusions (1B)
Glucose Control
• After initial stabilization
– Glcose be maintained <150 mg/dl
– Continuous infusion insulin and glucose or
feeding (enteral preferred)
– Monitoring
• Initially: q30-60 mins
• After stabilizaiton: q4h
Van den Berghe et al. NEJM, 2001
Finney et al. JAMA, 2003
Krinsley. Mayo Clin Proc. 2004
2008 update

Renal Replacement
• Absence of hemodynamic instability
– Intermittent hemodialysis and continuous venovenous
filtration equal (CVVH)

Grade 2B

• Hemodynamic instability
– CVVH preferred --- to facilitate management
of fluid balance in septic patients, no improved in
regional perfusion and survival benefit
Grade 2D
Bicarbonate Therapy
 Bicarbonate therapy not recommended to
improve hemodynamics in patients with
hypoperfusion-induced lactic acidemia pH
• 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
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
2008 update

Stress Ulcer prophylaxis

• H2 blocker Grade 1A

• Proton pump inhibitor Grade 1B

• 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

Intensive Care Med 2006;32:1151-1158

Monitoring a Child With Septic
• Frequent monitoring is
MOST IMPORTANT to recognise and Rx
1. Pulse 5. Urine output.
2. BP6. ABG
3. Level of
consciousness 7. PT/PTT/PC
4. 02 saturation 8. CVP
Management- summary.
Five important points
1. ABC, supplement 02 always.
2. IV or IO access and fluid resuscitation upto
60 mL/Kg.
3. Early dopamine infusion @10µg/Kg/min
4. Empirical antibiotic.
5. Frequent monitoring.
Summary: gain in mortality in
• 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% (-
– Valles J et al. Chest 2003; 123: 1615-1624
A clinician, armed with the sepsis bundles, attacks the three heads of severe sepsis:
hypotension, hypoperfusion and organ dysfunction. Crit Care Med 2004; 320(Suppl):S595-
Thanks for your attention
Avoid Sepsis