Presented by: Kiung Hsia Ling

Date: 4/02/09
Contents
Introduction
Pathogenesis
Clinical & hemodynamic features
Therapeutic approach
Initial resuscitation
Hemodynamic support & adjunctive therapy
Other supportive therapy of severe sepsis
Fluid therapy
Vasopressors
Inotropic agents
References
Introduction
Septic shock is associated with a high
mortality rate
Approximately 500,000 cases of sepsis
syndrome annually, with mortality rates
ranging from about 30% at 1 month to 50% at
5 months
Approximately 25% of patients with sepsis
syndrome progress to septic shock
 ACCP/SCCM Consensus Conference
Definitions
Bacteremia Presence of viable bacteria in the blood
Systemic Systemic inflammatory response to a variety of severe clinical
inflammatory insults. The response is mainfested by two or more of the following
response syndrome conditions:
(SIRS) • temperature >38°C or <36°C
• heart rate >90 beats/min
• Respiratory rate >20 breaths/min
•WBC > 12,000 cells/mm2 , < 4,000 cell/mm3
Sepsis The systemic response to infection. The systemic response is
manifested by two or more of the following conditions as a result of
infection:
• temperature >38°C or <36°C
• heart rate >90 beats/min
• Respiratory rate >20 breaths/min
•WBC > 12,000 cells/mm2 , < 4,000 cell/mm3
Severe sepsis a/w organ dysfunction, hypoperfusion, or hypotension.
Hypoperfusion and perfusion abnormalities may include, but are
not limited to, lactic acidosis, oliguria, or an acute alteration in
mental status
Septic shock Sepsis with 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.
Patients who are on inotropic or vasopressor agents may not be
hypotensive at the time that perfusion abnormalities are measured.
Pathogenesis
Systemic Inflammation
or
Inflammatory
Response Diffuse Endothelial
Disruption
and Microcirculation
Defects

Seve Global Tissue Hypoxia

re and
Sepsi Organ Dysfunction
s
The initial response to an infecting organism is a
systemic response, with release of inflammatory
mediators and activation of the coagulation cascade.
Septic Shock Microvascular injury, thrombosis, and diffuse
endothelial disruption follow, resulting in imbalance
between oxygen delivery and oxygen consumption.
Global tissue hypoxia and cytophathic hypoxia
develop, leading to multiple organ dysfunction and
Clinical and Hemodynamic
Features
 Hemodynamic signs:
- hypotension
- tachycardia
- elevated CO
- low SVR
- low PCWP
 Even though CO is high, it is inadequate to maintain BP
that will perfuse the essential organs in the face of a
decreased SVR, evidenced by low oxygen delivery and
consumption
 Metabolic acidosis (anaerobic metabolism, due to
decreased perfusion causing lactic acidosis, and CO is
inadequate to meet oxygen requirements of the tissues)
 Decreased urine output (decreased renal perfusion)
 Altered sensorium (decreased cerebral perfusion)
 Increased WBC count
 Spiking fever
Therapeutic approach
Management of septic shock is directed toward
three primary areas:
1. Eradication of the source of infection
2. Hemodynamic support and control of tissue
hypoxia
3. Inhibition or attenuation of the initiators and
mediators of sepsos
Eradication the source of
infection
Leading cause: aerobic or anaerobic bacteria
Fungal, mycobacterial, rickettsial, protozoal, viral
infections may also be encountered
Use of an appropriate antibiotic regimen is a/w
significant increase in survival
Selection of antibiotics should take into account the
presumed site of infection; whether the infection is
community- or hospital-acquired; recent invasive
procedures, manipulations, or surgery; any
predisposing conditions; and the likelihood of drug
resistance
If the source of infection is unclear, early institution of
broad-spectrum antibiotics is generally recommended
while awaiting culture results
A combination of two antibiotics is suggested to
provide for possible synergy and to reduce the
emergence of resistant organisms
 Empirical antimicrobial
recommendations
Sepsis Recommended Antimicrobial Comments
Source Regimen (Standard Adult
Dosing )
Unknown Vancomycin 1g BD & levofloxacin Consider abdominal/pelvic
source 750mg OD & gentamicin 7mg/kg imaging if physical examination,
OD chest radiograph, and urinalysis
do not reveal an infection source

Community Vancomycin 1g BD & levofloxacin Consider Pneumocystis carinii

-acquired 750mg OD (& gentamicin 7mg/kg pneumonia treatment in AIDS
pneumonia OD if recent patietns and obtain an
hospitalization/nursing home echocardiogram to evaluate
residence, recent antibiotic use, endocarditis with septic emboli in
or bronchiectasis) intravenous drug users
Meningitis Vancomycin 1g BD & ceftriaxone If altered mental status or focal
2g BD neuroloigc abnormalities,
consider adding acyclovir
(10mg/kg TDS) to treat herpes
encephalitis
 Empirical antimicrobial
recommendations
Sepsis Recommended Antimicrobial
Source Regimen (Standard Adult
Dosing )
UTI Piperacillin/tazobactam 3.375g
QID & gentamicin 7mg/kg OD
Intraabdo Piperacillin/tazobactam 3.375g
minal/pelvi QID & gentamicin 7mg/kg OD
c infection
Skin and Vancomycin 1g BD &
soft tissue piperacillin/tazobactam 3.375g
infection/n QID & clindamycin 900mg TDS
ecrotizing
infection
Comments
If nitrite production or Gram’s
stain suggests
Enterobacteriaceae, levofloxacin
or ceftriaxone can be substituted
for gentamicin
Obtain imaging to identify
infection focus and potential for
percutaneous or open drainage,
and/or surgical cosultation
For suspected necrotizing
infections, obtainsurgical
consultation for tissue
debridement as soon as possible
Initial Resuscitation
Immediate goal:
- maximize oxygen delivery to the tissues
Fluid resuscitation: mainstay of therapy &
improves oxygen delivery by increasing CO
Inotropic & vasopressor: required for
additional cardiovascular support
A favourable response to immediate
resuscitative efforts: reversal or halt in the
progression of the metabolic acidosis,
improved sensorium, and increased UO
 Initial Resuscitation & Infection
Issues
Initial resuscitation (first 6 hours)
- Begins resuscitation immediately in patients with
hypotension or elevated serum lactate > 4mmol/L
- Resuscitation goals:
 CVP 8-12 mmHg
 MAP ≥ 65 mmHg
 UO ≥ 0.5 ml/kg/hr
 central venous oxygen saturation ≥ 70%
- If venous oxygen saturation target is not achieved
 consider further fluid
 transfuse packed red blood cells if required to Hct ≥ 30%
 start dobutamine infusion, max: 20µg/kg/min
 Initial Resuscitation & Infection
Issues
Antibiotic therapy
- Begin IV antibiotics as early as possible & always
within the first hour of recognizing severe sepsis & septic
shock
- Broad-spectrum: one or more agents active against likely
bacterial/fungal pathogens & with good penetration into
presumed source
- Reassess antimicrobial regimen daily to optimize efficacy,
prevent resistance, avoid toxicity, and minimize costs
- Duration of therapy typically limited to 7-10 days; longer if
response is slow or there are undrainable foci of infection or
immunologic deficiencies
 Hemodynamic Support & Adjunctive
Therapy
Fluid therapy
- Fluid-resuscitate using crystalloids or colloids
- Target a CVP ≥ 8 mmHg (≥ 12 mmHg if
mechanically
ventilated)
- Use a fluid challenges of 1000mL of crystalloids or
300-
500mL of colloids over 30 mins.
- Rate of fluid administration should be reduced if
cardiac
filling pressures increase without concurrent
hemodynamic
improvement
 Hemodynamic Support & Adjunctive
Therapy
Vasopressors
- Maintain MAP ≥ 65mmHg
- Norepinephrine and dopamine centrally administered are
the initial vasopressors of choice
- Epinephrine, phenylephrine, or vasopressin should not be
administered as the initial vasopressor. Vasopressin 0.03
units/min may be subsequently added to norepinephrine
with anticipation of an effect equivalent to norepinephrine
alone
- Use epinephrine as the first alternative agent in septic shock
when blood pressure is poorly responsive to
norepinephrine or dopamine
- Do not use low-dose dopamine for renal protection
 Hemodynamic Support & Adjunctive
Therapy
Inotropic therapy
- Use dobutamine in patients with myocardial dysfunction as
supported by elevated cardiac filling pressures and low CO
- Do not increase CI to predetermined supranormal levels
Steroids
- Consider IV hydrocortisone when hypotension responds
poorly to adequate fluid resuscitation & vasopressors
- Hydrocortisone is preffered to dexamethasone
- Steroid therapy may be weaned one vasopressors are no
longer required
- Hydrocortisone dose should be ≤ 300mg/day
 Other Supportive Therapy of
Severe Sepsis
Blood product administration
- Give RBCs when Hgb decreases to <7.0 g/dL to target of 7-9
g/dL . A higher Hgb level may be required in special
circumstances (e.g. myocardial ischaemia, severe
hypoxemia, acute hemorrhage, cyanotic heart disease,
lactic acidosis)
- Do not use erythropoietin to treat sepsis-related anemia
- Do not use antithrombin therapy
- Administer platelets when:
 counts are <5000/mm3 regardless of bleeding
 counts are 5000-30,000/mm3 & there is significant bleeding
risk
 Other Supportive Therapy of
Severe Sepsis
Mechanical ventilation of sepsis-induced ALI/ARDS
- Target a tidal volume of 6mL/kg body weight
- Set PEEP to avoid extensive lung collapse at end-expiration
- Maintain mechanically ventilated patients in a
semirecumbent position (head of the bed raised to 45°)
- Do not use a pulmonary artery catheter for the routine
monitoring
 Glucose control
- Use IV insulin to control hyperglycemia
- Aim to keep blood glucose < 150mg/dL
- Provide a glucose calorie source and monitor BG values
every 1-2 hours (4 hrs when stable)
 Other Supportive Therapy of
Severe Sepsis
Bicarbonate therapy
- Do not use bicarbonate therapy for the purpose of
improving hemodynamics or reducing vasopressor
requirements when treating hypoperfusion-induced lactic
acidemia with pH ≥ 7.15
Deep vein thrombosis prophylaxis
- Use either low-dose UFH or LMWH, unless contraindicated
- Use a mechanical prophylactic device, such as compression
stockings, when heparin is contraindicated
- Use a combination of pharmacologic & mechanical therapy for
patients who are at very high risk for DVT
- In patietns at very high risk, LMWH should be used rather than
UFH
 Other Supportive Therapy of
Severe Sepsis
Stress ulcer prophylaxis
- Using H2 blocker or PPI
- Benefits of prevention of upper GI bleeding must
be
weighed against the potential for development of
ventilator-acquired pneumonia
 Fluid Therapy
First parameter to target in hemodynamic optimization is
intravascular volume with the use of fluid therapy
Choice: crystalloids & colloids
No outcome benefit has been demonstrated in using colloids
compared to crystalloids with respect to mortality or hospital
length of stay
The volume of crystalloids required may be 2 to 3 times than
colloids to restore optimal volume
E.g. 1 L of NS adds 275mL to the plasma volume, whereas 1 L
of 5% albumin will increase plasma volume by 500mL
For patients with low CVP & concurrent pulmonary edema, a
colloid may be combined with crystalloid to avoid large
volume of crystalloid & to rapid achieve the CVP goal
 Vasopressors
Norepinephrine
- Potent α-adrenergic agent with less pronouced β-
adrenergic activity
- Useful when potent vasoconstriction of peripheral vascular
beds is desired
- 0.01-3µg/kg/min: increase BP with little change in HR or CI
- More potent than dopamine in refractory septic shock
- Despite earlier concern of decreased renal blood flow a/w
norepinephrine, data in humans & animals demonstrate a
norepinephrine-induced renal blood flow as well as urine &
cardiac output
 Vasopressors
Epinephrine
- Nonspecific α- and β-adrenergic agonist
- Capable of increasing CI & producing significant
peripheral vasoconstriction in dose of 0.1-
0.5µg/kg/min
- Undesirable effects: propensity to increase
lactate level & to
impair blood flow to the splanchnic system
- Reserved for patients who failed to respond to
traditional
therapies for increasing or maintaining BP
 Vasopressors
Phenylephrine
- Selective α1-agonist, rapid onset, short duration, primary
vascular effect
- Appears useful when tachycardi limits the use of other
vasopressors
Vasopressin
- α-agonist, deficiency in many septic shock patients, is an
endogenously produced hormone
- Not considered a first-line agent
- May a/w a decrease in CO
- Commonly used in combination with other vasoactive
agents
 Inotropic Agents
Dopamine
- α- and β-adrenergic agent with dopaminergic activity,
appears to increase MAP effectively in patients who remain
hypotension with reduced cardiac function after aggressive
fluid resuscitation
- Initial choice in sepsis because of combined vasopressor &
inotropic effects
- Low-dose dopamine: 1-5 µg/kg/min, effective in
maintaining renal perfusion
- Higher dose: >5 µg/kg/min, exhibit α and β activity & are
used frequently to support BP & to improve cardiac
function such as increase in CI
 Inotropic Agents
Dobutamine
- β-adrenergic inotropic agent
- Preferred drug for improvement of CO & oxygen
delivery,
particularly in early sepsis before significant
peripheral
vasodilation has occurred
- 2-20 µg/kg/min: increase CI (ranging from 20-66%).
However, HR often increase significantly
- Should be considered in severely septic patients
with
adequate filling pressure & BP but low CI
References
Severe sepsis and septic shock: review of the literature and emergency
department mangement guidelines. N. Bryant, R. Emanuel, A. Fredrick,
M. Gregory, A. Edward, T. Stephen, et.al. Annals of Emergency Medicine
2006;48(1):28-54
Surviving sepsis campaign: International guidelines for management of
severe sepsis and septic shock: 2008. D. Phillip, L. Mitchell, C. Jean, B.
Julian, P. Margaret, J. Roman, et.al. Critical Care Medicine 2008;34:1-33
Adams VR, Yee GC. Lymphoma. In: Dipiro JT, Talbert RL, Yee GC, et al.
Pharmacotherapy: a pathophysiologic approach. 6th edition. New York:
McGraw-Hill; 2006. Chapter 117 pg 2131-42
Koda-Kimble MA. Applied therapeutics: the clinical use of drugs.
8thedition. USA: Lippincott Williams &Wilkins; 2005. Chapter 22: pg 1-37