SUBJECT: Medicine II DATE: July 2, 2008

TOPIC: Sepsis and Septic Shock

LECTURER: Dr. Gabriel
TRANSGROUP: shar, maqui, viki

• Microvascular abnormalities
EPIDEMIOLOGY • Intracellular defects
• 500,000 – 750,000 cases annually in the United
States and rising
• Most common cause of death in non-coronary ICU
and two-thirds of cases occur in hospitalized
C. Toxins
patients
• Gram (+) organisms (Staph and Strep)
• Increasing incidence of severe sepsis is attributable
liberate exotoxin
to the aging population with chronic diseases
• Gram (-) organisms produce endotoxin
• Widespread use of antimicrobial agents, indwelling
catheters, mechanical devices and ventilators • Pseudomonas produces both endotoxin and
increase incidence exotoxin
• 30% mortality when shock is present • Endotoxin is a heat stable polysaccharide
derived from the cell wall of a gram (-)
• Severe sepsis $22K/pt, $16 billion/year
bacteria

DEFINITIONS
• Endotoxin – lipid moiety – lipid A = active
part
• Systemic Inflammatory Response System
• Core oligosaccharide and polysaccharide are
(SIRS) probably inert
o Widespread inflammatory response
o Two or more of the following
TIME-COURSE OF INFLAMMATORY
 Temp > 38°C or ˂ 36°C RESPONSE DURING SEPSIS
 Heart Rate > 90 bpm
 Tachypnea (RR > 20) or
hyperventilation (PaCoz ˂ 32 mmHg)
 WBC > 12,000 cells/mm3, < 4000
cells/mm3 or presence of >10%
immature neutrophils
• Sepsis
o SIRS + definitive source of infection
• Severe Sepsis
o Sepsis + organ dysfunction, hypoperfusion, or
hypotension
o Hypoperfusion and perfusion abnormalities may
include but not limited to lactic acidosis,
oliguria or an acute mental state.
• Septic Shock
o Sepsis + hypotension despite fluids
o Perfusion abnormalities
 Lactic acidosis
 Oliguria
 Acute AMS
• Multiple Organ System Failure
o Abnormal function of two or more organs such
that homeostasis cannot be achieved THE CASCADE OF EVENTS IN SIRS
without intervention Lipopolysaccharide + lipopolysaccharide binding
protein bind to macrophages then inflammatory
PATHOPHYSIOLOGY cascade stimulated by TNF.
Systemic Inflammatory response System (SIRS)
1.Activation of the complement cascade leads to
• Severe infection – bacteremia/endotoxemia activation of leukocytes, release of inflammatory
• Large areas of devitalized tissue – surgery/trauma mediators such as proteases and oxygen free
radicals. This leads to localized tissue damage
A. Systemic activation of leukocytes leads to the and increased capillary permeability.
release of a variety of mediators 2. Tumor necrosis factor (TNF) plays a pivotal
• TNF – α, IL-1, IL-6 role via the cyclooxygenase pathway.
• Complement system (C5 alpha) 3. Interleukin 1 (IL-1) – stimulates T helper cells
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• Bacterial factors to produce IL-2 which stimulates cytotoxic T

B. Dissemination of this response cells.
• Hemodynamic changes 4. IL-1 and TNF act synergistically
 a.Induction of cyclooxygenase • Ventricular dilatation occurs due to decreased
b.Platelet activation factor (PAF) compliance
c. Nitric oxide synthase
5. IL-6 and IL-8 are involved in the reparative Cardiac dysfunction may also be affected by:
process they cause and down regulation of TNF • Acidosis
and IL-1 production. • Hypoxemia
• Myocardial edema
Arachidonic Acid Metabolites
• Prostacyclin (PGI2) – vasodilator, inhibits Microcirculatory Changes = Capillary Leak Syndrome
platelet activity • Vasodilatation
• Thromboxane A2 – vasoconstrictor and platelet • Maldistribution of flow
aggregator • A-V shunting
• Increased capillary permeability + interstitial
edema
Platelet Activation Factor • Decreased oxygen extraction
• Hypotension • Primary defect of oxygen utilization at cellular
• Increased vascular permeability level
• Platelet aggregation

Cell Necrosis/Hypoxia/Ischemia/Sepsis/Acidosis Capillary endothelial injury follows:

Lead to release of lysosomal enzymes • DIC
• Directly cytotoxic • Microemboli
• Myocardial depression • Release of vasoactive components
• Coronary vasoconstriction • Complement activation
• Activation of kininogens and kinis • Extravascular migration of leukocytes
• Vasodilation
• Increased capillary refill N.B. capillary permeability is increased so that fluid is
• Activation of clotting systems lost into the interstitial space leading to
hypovolemia/interstitial edema/organ dysfunction.
Endothelium
The vascular endothelium is an organ which Reperfusion of the microcirculation leads to the
regulates: generation of large quantities of oxygen free radicals
leading to tissue damage, particularly to the gut
• Blood vessel tone
mucosa.
• Vascular permeability
• Coagulation Organ Dysfunction:
• Angiogenesis The brain and kidneys are normally protected from
• WBC and platelet activity swings in blood pressure by autoregulation:
• Phagocytosis of bacteria 1. In early sepsis – autoregulation curve shifts
The endothelium produces a number of vasoactive rightwards (due to and increase in sympathetic
substances tone)
• Nitric oxide (EDRF) 2. In late sepsis – vasoparesis occurs
• Prostacyclin
- Autoregulation fails
• Endothelin – 1
- “steal phenomena” may occur (areas of
ischemia may have their blood stolen by
Nitric Oxide (NO)
areas with good perfusion)
• Produced from L-arginine by nitric oxide
synthetase (NOS) A. Heart
• Activity is via cGMP
- Myocardial O2 supply is dependent on diastolic
BP
Effect
- Circulating myocardial depressant factor
• Vasodilation
• Inhibition of platelet aggregation B. Lungs
- Ventilation/perfusion mismatches
THE CASCADE OF EVENTS IN SEPTIC SHOCK - Initially due to increased dead space
The dominant hemodynamic feature in septic shock is - Subsequently due to shunt
peripheral vascular failure. - Acidosis – tachypnea, decreased PaCO2
• Leading to persistent hypotension resistant to - Nosocomial pneumonia approximately 70%
vasoconstrictors
• Usually high output due to low SVR/increased HR C. Kidneys
• Nevertheless, there usually is a myocardial - Oliguria
depressant factor present: o Pre-renal (by a long way most common)
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o Decreased SV decreased left ventricular o Renal

stroke work: Tx = volume loading o Post renal
 - Pre-renal failure due to intravascular - Hyperglycemia due to sepsis and
dehydration, circulating nephrotoxins, drugs catecholamines (both cause insulin resistance)
- Lactic acidosis
D. Liver - Muscular breakdown
- ICU jaundice - Generalized catabolic state
- Uncontrolled production of inflammatory
cytokines by the Kuppfer cells, primed by SIGNS AND SYMPTOMS OF SEPSIS
ischemia and stimulated by endotoxin (derived
• Temperature increased or decreased
from the gut), leads to cholestasis and
hyperbilirubinemia • WBC count increased or decreased
• Rigors
E. Splanchnic Circulation • Sweating
- GUT mucosa is usually protected from injury by • Nausea and vomiting
autoregulation • Tachycardia
- Hypotension and hypovolemia leads to • Hypotension
superficial mucosal injury which leads to • Tachypnea (acute lung injury)
atrophy and translocation of bacteria into the • Warm pink peripheries
portal circulation and stimulate liver • Confusion
macrophages causing cytokine release and • Oliguria
amplification of SIRS
• Increased glucose
• Increased lactate
F. CNS
- Confusion/stupor/coma secondary to: • Increasingly negative base excess
o Hypoperfusion injury • Decreased albumin
o Septic encephalopathy • Increased INR. Increased aPTT, decreased
o Metabolic encephalopathy platelets, DIC
o drugs • Jaundice

G. Metabolic

Microbial TNF
Adaptive
Cytokines
Agents Immunity Complement C5a
Innate Immune Release of
Endotoxin (LPS) Coagulation
Response Mediators
Factors
Mechanism Activation of
Vascular
Sepsis Endothelium
Phospholipid –
DIC Man Derived
DEATH Mediators
SSXs:
Fever Resuscitation:
Myalgia ABC
Tachycardia Restore tissue
Tachypnea perfusion
Leukocytosis Appropriate
Somnolence antibiotics
Tissue
oxygenation
Steroids
Nutrition

WORK-UP FOR SEPTIC SHOCK - Partial thromboplastin time

Laboratory Studies - Fibrinogen level
- CBC with differentials
- Hemoglobin, hematocrit, platelet Blood Cultures
Urinalysis/Urine Culture
Comprehensive Chemistry Panel Gram’s Stain or Culture for sputum, abscesses, CSF
- Sodium and chloride level
- Bicarbonate Imaging Studies
- BUN and creatinine - Chest X-ray
- Glucose - X-ray of the abdomen
- Liver function test - Abdominal ultrasonography
- Serum lactate levels - Abdominal CT scan
- Plain radiograph of the extremities
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Coagulation Studies
- Prothrombin time Procedures
 - Orotracheal intubation •Restore tissue perfusion
- Mechanical ventilation •Identify and eradicate source of infection
- Urinary foley catheter •Assure adequate tissue oxygenation
- Cutaneous or soft tissue drainage •Activated protein C
- Lumbar puncture •Steroids
- Intravenous access for CVP
•Glucose control
•Nutrition
MANAGEMENT OF SEPSIS
•Resuscitate: ABCs

SEPTIC SHOCK ALGORITHM EXAMPLE

Consider introducing activated

protein C for 96h if no risk of
bleeding and no clinical Beyond ICU
improvement Rehabilitatio
n program

Referral to Checking availability of antibiotics and

ICU if possible narrowing spectrum
Surgical relook if needed

Shock onset
Respirator
y support

Oh 6h 24-48 Day
h
Antibiotics
Broad spectrum
Surgical cure if
needed
Non-refractory
septic shock
Hemodynami
c Fluid Consider weaning from
challeng vasopressors and other life
resuscitation
Refractory septic es
shock Stop
steroids
Fluid
challenges
Adrenocorticotrophi Normal adrenal
c hormone test function
Vasopressors if Start low-dose
patient remains steroids
hypotensive
Stop
steroids
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