2. Incidence of sepsis has risen dramatically
 increase in the number of invasive procedures
 immunosuppressive therapy
 advancing age of population
In United States  approximately 750,000
cases/year and the frequency is increasing
At least 225,000 are fatal.
N Engl J Med 2003;348:1546-54.

3.  Septic shock and multiorgan dysfunction are the most
common causes of death in patients with sepsis.
 The mortality rate
 severe sepsis 25 - 30%1
 septic shock 40 - 70%2
 The number of sepsis cases is projected to grow at a
rate of 1.5% per year, making a total of nearly 18 million
new cases to occur worldwide each year.
1.N Engl J Med 2001;344:699-709.
2.Am J Respir Crit Care Med 2003;168:165-72.

4. 1. Systemic Inflammatory Response
Syndrome (SIRS)
Two or more of the following
- BT > 38 c or < 36 c
- Heart rate > 90 beats/min
- Respiratory Rate > 20 breaths per min or PaCO2 < 32 mmHg
- White Cell Count > 12,ooo cells/mm3 , < 4,000 cells/mm3
or > 10% immature forms
2. Sepsis
SIRS resulting from documented infection.
Crit care Med 1992;20:864-874

7. SIRS / Sepsis
Bacteremia
Other
(septicemia)
SIRS Trauma
Infection Fungal Sepsis
Parasite. Burns
Vir.
Other Pancreatitis
*Severe SIRS/Sepsis includes some evidence of organ failure

9. 4. Septic shock
Sepsis with hypotension ( arterial blood pressure < 90 mmHg
systolic , or 40 mmHg less than patient’s normal blood pressure )
for at least 1 hr despite adequate fluid
or
Need for vasopressors to maintain systolic blood pressure
>= 90 mmHg or MAP >= 70 mmHg
5. Refractory septic shock
Shock refractory to conventional therapy (intravenous fluids
and inotropic/vasoactive agents) within one hour.
6. Multiple-organ dysfunction syndrome
( MODS )
Dysfunction of more than one organ , requiring intervention to
maintain homeostasis
Crit care Med 1992;20:864-874

10. SIRS / Sepsis
Bacteremia
Other
(septicemia)
SIRS Trauma
Infection Severe
Fungal Sepsis
sepsis/MODS
Parasite. Burns
Vir.
Other Pancreatitis
*Severe SIRS/Sepsis includes some evidence of organ failure

11. Sepsis: Defining a Disease Continuum
Insult SIRS Sepsis Severe Sepsis
Sepsis with 1 sign of organ
failure
Cardiovascular (refractory
hypotension)
Renal
Respiratory Shock
Hepatic
Hematologic
Bone et al. Chest. 1992;101:1644; Wheeler and
CNS
Bernard. N Engl J Med. 1999;340:207. Metabolic acidosis

14. Presumed sites of infection in patients with culture-positive severe
sepsis. Bars show the means of data from four studies. Brackets show
the minimum and maximum values reported. Note that the lung and
abdomen are the most common primary sites.

17. TLR = toll-like receptors; NF-κB = cytosolic nuclear factor κB; TNF-α = tumor
necrosis factor α; iNOS = inducible nitric oxide synthase.

18.  TNF-α and interleukin-1β are proinflammatory cytokines
that activate the adaptive immune response but also cause
both direct and indirect host injury.
 Interleukin-10 is an antiinflammatory cytokine that
inactivates macrophages and has other antiinflammatory
effects.
 Proteases, oxidants, prostaglandins, and leukotrienes
injure endothelial cells, leading to increased permeability,
further vasodilation, and alteration of the procoagulant–
anticoagulant balance.
 Cytokines also activate the coagulation cascade.

19. TFPI=tissue factor–pathway inhibitor, PAI-1=plasminogen-activator inhibitor 1,
t-PA=tissue plasminogen activator , EPCR = endothelial protein C receptor

21. Thomas M. Terry, The University of Connecticut.

23. Sepsis Resuscitation Bundle
Sepsis Management Bundle

24. Sepsis Resuscitation Bundle:
1. Serum lactate measured
2. Blood cultures obtained prior to antibiotic administration
3. From the time of presentation, broad-spectrum antibiotics
administered within 3 hours for ED admissions and 1 hour for non-
ED ICU admissions
4. In the event of hypotension and/or lactate > 4 mmol/L (36 mg/dl):
 Deliver an initial minimum of 20 ml/kg of crystalloid (or colloid equivalent)
 Apply vasopressors for hypotension not responding to initial fluid resuscitation
to maintain mean arterial pressure (MAP) > 65 mm Hg
5. In the event of persistent hypotension despite fluid resuscitation
(septic shock) and/or lactate > 4 mmol/L (36 mg/dl):
 Achieve central venous pressure (CVP) of > 8 mm Hg
 Achieve central venous oxygen saturation (ScvO2) of > 70%
www.ihi.org/IHI/Topics/CriticalCare/Sepsis

26. Sepsis Management Bundle:
1. Low-dose steroids administered for septic shock in
accordance with a standardized ICU policy
2. Drotrecogin alfa (activated) administered in
accordance with a standardized ICU policy
3. Glucose control maintained > lower limit of normal,
but < 150 mg/dl (8.3 mmol/L)
4. Inspiratory plateau pressures maintained < 30 cm
H2O for mechanically ventilated patients
www.ihi.org/IHI/Topics/CriticalCare/Sepsis

27.  Secondary to anaerobic metabolism due to
hypoperfusion.
Limitations:
 Elevated lactate levels can also result from decreased
clearance by the liver.
www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/IndividualChanges/SerumLactateMeasur
ed.htm

28. Implications:
 Given the high risk for septic shock, all patients with
lactate > 4 mmol/L (36 mg/dl) will enter the early
goal-directed therapy portion of the Severe Sepsis
Resuscitation Bundle, regardless of blood pressure.
www.survivingsepsis.org/Bundles/Individual_Changes/Pages/serum_lactate.aspx

29. Turnaround Time
 Serum lactate must be available in your institution
with rapid turnaround time (within minutes) to
effectively treat severely septic patients.
 An arterial blood gas analyzer located in the clinical
laboratories usually accomplishes this.
www.survivingsepsis.org/Bundles/Individual_Changes/Pages/serum_lactate.aspx

30.  Tips
 If not rapidly available in your institution, invest in
equipment to make rapid assessment possible.
 This should be presented to hospital and laboratory
administration as a present standard of care.
 Create a standardized protocol to manage severe sepsis
that includes measurement of serum lactate.
 Attach a lactate blood tube to blood culture tubes to
increase the number of patients that are screened.
www.survivingsepsis.org/Bundles/Individual_Changes/Pages/serum_lactate.aspx

31. : Indicates a strong recommendation or “we
recommend”
 : Indicates a weak recommendation or “we suggest”

32. The Problem
 Inconsistency in the early diagnosis of severe sepsis and
septic shock
 Frequent inadequate volume resuscitation without defined
endpoints
 Late or inadequate use of antibiotics
 Frequent failure to support the cardiac output when
depressed
 Frequent failure to control hyperglycemia adequately
 Frequent failure to use low tidal volumes and pressures in
acute lung injury
 Frequent failure to treat adrenal inadequacy in refractory
shock

33.  Begin resuscitation immediately in patients with
hypotension or elevated serum lactate ≥ 4mmol/L; do
not delay pending ICU admission. (1C)
 Resuscitation goals: (1C)
• Central venous pressure (CVP) 8–12 mm Hg*
• Mean arterial pressure ≥ 65 mm Hg
• Urine output ≥ 0.5 mL.kg-1.hr-1
• Central venous (superior vena cava) oxygen saturation(ScVO2) ≥
70%,
or mixed venous (SvO2)≥ 65%
 If venous O2 saturation target not achieved: (2C)
• Consider further fluid
• Transfuse packed red blood cells if required to hematocrit of ≥ 30%
and/or
• Dobutamine infusion max 20 μg.kg-1.min-1
* A higher target CVP of 12-15 mmHg is recommended in the presence of mechanical
ventilation or pre-existing decreased ventricular compliance.

34.  Obtain appropriate cultures before starting
antibiotics provided this does not significantly
delay antimicrobial administration.(1C)
• Obtain two or more blood cultures (BCs)
• One or more BCs should be percutaneous
• One BC from each vascular access device in place >48
hours
• Culture other sites as clinically indicated
 Perform imaging studies promptly in order to
confirm and sample any source of infection (1C)

35.  If the same organism is recovered from both cultures,
the likelihood that the organism is causing the severe
sepsis is enhanced.
 If the culture drawn through the vascular access device
is positive > 2 hours earlier than the peripheral blood
culture, it may offer support that the vascular access
device is the source of the infection.

36. Indications:
 Fever
 Chills
 Hypothermia
 Leukocytosis
 Left shift of neutrophils
 Neutropenia
 Unexplained organ dysfunction, e.g., renal failure or signs
of hemodynamic compromise.
 Blood cultures should be taken as soon as possible
after the onset of fever or chills.

37. Begin intravenous antibiotics as early as
possible, and always within the first hour of
recognizing severe sepsis (1D) and septic
shock. (1B)
Broad-spectrum: one or more agents active
against likely bacterial/fungal pathogens
and with good penetration into presumed
source. (1B)
Consider combination therapy in
Pseudomonas infections. (2D)
Consider combination empiric therapy in
neutropenic patients. (2D)

38.  Harbarth S. Am J Med 2003;115(7):529–35
 Inappropriate initial antibiotic therapy was associated
with excess mortality (OR 1.8)
 Leibovici L. J Intern Med 1998;244:379–86.
 Appropriate empiric antibiotic treatment resulted in a
decrease in mortality from 34%  20%.
 Fatality with inappropriate antibiotics and septic shock
 OR 1.6

39.  Reassess antimicrobial regimen daily to optimize
efficacy, prevent resistance, avoid toxicity, & minimize
costs. (1C)
 Combination therapy no more than 3-5 days and de-
escalation following susceptibilities. (2D)
 Duration of therapy typically limited to 7–10 days;
longer if response slow, undrainable foci of infection,
or immunologic deficiencies. (1D)
 Stop antimicrobial therapy if cause is found to be non-
infectious. (1D)

40.  A specific anatomic site of infection should be
established as rapidly as possible (1C) and within
the first 6 hours of presentation. (1D)
 Implement source control measures as soon as
possible following successful initial resuscitation.
(1C)
 Exception: infected pancreatic necrosis, where
surgical intervention best delayed. (2B)
 Choose source control measure with maximum
efficacy and minimal physiologic upset. (1D)
 Remove intravascular access devices if potentially
infected. (1C)

41.  Fluid-resuscitate using crystalloids or colloids. (1B)
 Target a CVP of ≥ 8mmHg (≥12mmHg if mechanically
ventilated). (1C)
 Use a fluid challenge technique while associated with
a hemodynamic improvement. (1D)
 Give fluid challenges of 1000 mL of crystalloids or
300–500 mL of colloids over 30 minutes. More rapid
and larger volumes may be required in sepsis-induced
tissue hypoperfusion. (1D)
 Rate of fluid administration should be reduced if
cardiac filling pressures increase without concurrent
hemodynamic improvement. (1D)

42.  Administration of 20 ml/kg of crystalloid as a fluid
challenge in cases of suspected hypovolemia or serum
lactate greater > 4 mmol/L (36 g/dl).
 A colloid equivalent is an acceptable alternative to
crystalloid, and an equivalent dose generally ranges
from 0.2 g/kg to 0.3 g/kg depending upon the colloid.

43.  The Saline vs. Albumin Fluid Evaluation (SAFE) study
has been completed, having enrolled 7,000 patients.
 The results of this study showed identical mortality
rate in patients receiving albumin or 0.9% sodium
chloride.
NEJM. 2004;350:2247–56.

44.  Maintain MAP ≥ 65mmHg. (1C)
 Norepinephrine or dopamine centrally administered
are the initial vasopressors of choice. (1C)
 Epinephrine, phenylephrine, or vasopressin should
not be administered as the initial vasopressor in
septic shock. (2C)
 Use epinephrine as the first alternative agent in septic
shock when blood pressure is poorly responsive to
norepinephrine or dopamine. (2B)
 Do not use low-dose dopamine for renal protection.
(1A)
 In patients requiring vasopressors, insert an arterial
catheter as soon as practical. (1D)

46.  Physiologic goal-directed resuscitation in sepsis
 Discussed and debated extensively in critical care
 Only a randomized clinical trial has been able to show a
survival benefit from a specific protocol.

47. Outcome before
and after
systematic
initiation of this
protocol have
supported this
observation.

53.  Data synthesized from nine randomized controlled
trials demonstrate a clear survival benefit afforded by
quantitative resuscitation to treat sepsis at or near the
time of recognition.
 Our results provide the strongest support to date for
the Surviving Sepsis Campaign recommendation of
providing quantitative resuscitation at the time of
severe sepsis recognition