SUBJECT: Medicine II DATE: July 2, 2008

TOPIC: Sepsis and Septic Shock

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

• Hemodynamic changes
EPIDEMIOLOGY
• Microvascular abnormalities
• 500,000 – 750,000 cases annually in the United • Intracellular defects
States and rising
• Most common cause of death in non-coronary ICU
and two-thirds of cases occur in hospitalized
patients
• Increasing incidence of severe sepsis is attributable C. Toxins
to the aging population with chronic diseases • Gram (+) organisms (Staph and Strep)
• Widespread use of antimicrobial agents, indwelling liberate exotoxin
catheters, mechanical devices and ventilators • Gram (-) organisms produce endotoxin
increase incidence • Pseudomonas produces both endotoxin and
• 30% mortality when shock is present exotoxin
• Severe sepsis $22K/pt, $16 billion/year • Endotoxin is a heat stable polysaccharide
derived from the cell wall of a gram (-)
bacteria
DEFINITIONS
• Endotoxin – lipid moiety – lipid A = active
• Systemic Inflammatory Response System
part
(SIRS)
o Widespread inflammatory response • Core oligosaccharide and polysaccharide are
o Two or more of the following probably inert
 Temp > 38°C or ˂ 36°C
TIME-COURSE OF INFLAMMATORY
 Heart Rate > 90 bpm
RESPONSE DURING SEPSIS
 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 without
intervention THE CASCADE OF EVENTS IN SIRS
Lipopolysaccharide + lipopolysaccharide binding
PATHOPHYSIOLOGY protein bind to macrophages then inflammatory
Systemic Inflammatory response System (SIRS) cascade stimulated by TNF.
• Severe infection – bacteremia/endotoxemia 1. Activation of the complement cascade leads to
• Large areas of devitalized tissue – surgery/trauma activation of leukocytes, release of
inflammatory mediators such as proteases and
A. Systemic activation of leukocytes leads to oxygen free radicals. This leads to localized
the release of a variety of mediators tissue damage and increased capillary
• TNF – α, IL-1, IL-6 permeability.
•
Complement system (C5 alpha) 2. Tumor necrosis factor (TNF) plays a pivotal
Page4

• Bacterial factors role via the cyclooxygenase pathway.

B. Dissemination of this response
 3. Interleukin 1 (IL-1) – stimulates T helper cells • Usually high output due to low SVR/increased
to produce IL-2 which stimulates cytotoxic T HR
cells. • Nevertheless, there usually is a myocardial
4. IL-1 and TNF act synergistically depressant factor present:
a. Induction of cyclooxygenase o Decreased SV decreased left ventricular
b. Platelet activation factor (PAF) stroke work: Tx = volume loading
c. Nitric oxide synthase • Ventricular dilatation occurs due to decreased
5. IL-6 and IL-8 are involved in the reparative compliance
process they cause and down regulation of TNF
and IL-1 production. Cardiac dysfunction may also be affected by:
• Acidosis
Arachidonic Acid Metabolites • Hypoxemia
• Prostacyclin (PGI2) – vasodilator, inhibits • Myocardial edema
platelet activity
Microcirculatory Changes = Capillary Leak Syndrome
• Thromboxane A2 – vasoconstrictor and
• Vasodilatation
platelet aggregator
• Maldistribution of flow
• A-V shunting
Platelet Activation Factor • Increased capillary permeability + interstitial
• Hypotension edema
• Increased vascular permeability • Decreased oxygen extraction
• Platelet aggregation • Primary defect of oxygen utilization at cellular
level
Cell Necrosis/Hypoxia/Ischemia/Sepsis/Acidosis
Lead to release of lysosomal enzymes
• Directly cytotoxic Capillary endothelial injury follows:
• Myocardial depression • DIC
• Coronary vasoconstriction • Microemboli
• Activation of kininogens and kinis • Release of vasoactive components
• Vasodilation • Complement activation
• Increased capillary refill • Extravascular migration of leukocytes
• Activation of clotting systems
N.B. capillary permeability is increased so that fluid is
lost into the interstitial space leading to
Endothelium
hypovolemia/interstitial edema/organ dysfunction.
The vascular endothelium is an organ which
regulates:
Reperfusion of the microcirculation leads to the
• Blood vessel tone generation of large quantities of oxygen free radicals
• Vascular permeability leading to tissue damage, particularly to the gut
• Coagulation mucosa.
• Angiogenesis
• WBC and platelet activity Organ Dysfunction:
• Phagocytosis of bacteria The brain and kidneys are normally protected from
The endothelium produces a number of vasoactive swings in blood pressure by autoregulation:
substances 1. In early sepsis – autoregulation curve shifts
• Nitric oxide (EDRF) rightwards (due to and increase in sympathetic
• Prostacyclin tone)
• Endothelin – 1 2. In late sepsis – vasoparesis occurs
- Autoregulation fails
Nitric Oxide (NO) - “steal phenomena” may occur (areas of
• Produced from L-arginine by nitric oxide ischemia may have their blood stolen by
synthetase (NOS) areas with good perfusion)
• Activity is via cGMP
A. Heart
Effect - Myocardial O2 supply is dependent on
• Vasodilation diastolic BP
• Inhibition of platelet aggregation - Circulating myocardial depressant factor

THE CASCADE OF EVENTS IN SEPTIC SHOCK B. Lungs

The dominant hemodynamic feature in septic shock is - Ventilation/perfusion mismatches
peripheral vascular failure. - Initially due to increased dead space
Page4

- Subsequently due to shunt

• Leading to persistent hypotension resistant to
vasoconstrictors - Acidosis – tachypnea, decreased PaCO2
- Nosocomial pneumonia approximately 70%
 C. Kidneys G. Metabolic
- Oliguria - Hyperglycemia due to sepsis and
o Pre-renal (by a long way most common) catecholamines (both cause insulin
o Renal resistance)
o Post renal - Lactic acidosis
- Pre-renal failure due to intravascular - Muscular breakdown
dehydration, circulating nephrotoxins, drugs - Generalized catabolic state

D. Liver SIGNS AND SYMPTOMS OF SEPSIS

- ICU jaundice • Temperature increased or decreased
- Uncontrolled production of inflammatory
• WBC count increased or decreased
cytokines by the Kuppfer cells, primed by
ischemia and stimulated by endotoxin • Rigors
(derived from the gut), leads to cholestasis • Sweating
and hyperbilirubinemia • Nausea and vomiting
• Tachycardia
E. Splanchnic Circulation • Hypotension
- GUT mucosa is usually protected from injury • Tachypnea (acute lung injury)
by autoregulation • Warm pink peripheries
- Hypotension and hypovolemia leads to • Confusion
superficial mucosal injury which leads to
• Oliguria
atrophy and translocation of bacteria into the
portal circulation and stimulate liver • Increased glucose
macrophages causing cytokine release and • Increased lactate
amplification of SIRS • Increasingly negative base excess
• Decreased albumin
F. CNS • Increased INR. Increased aPTT, decreased
- Confusion/stupor/coma secondary to: platelets, DIC
o Hypoperfusion injury • Jaundice
o Septic encephalopathy
o Metabolic encephalopathy
o drugs

Microbial Adaptive TNF

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

WORK-UP FOR SEPTIC SHOCK - Serum lactate levels

Laboratory Studies
- CBC with differentials Coagulation Studies
- Hemoglobin, hematocrit, platelet - Prothrombin time
- Partial thromboplastin time
Comprehensive Chemistry Panel - Fibrinogen level
- Sodium and chloride level
- Bicarbonate Blood Cultures
Urinalysis/Urine Culture
Page4

- BUN and creatinine

- Glucose Gram’s Stain or Culture for sputum, abscesses, CSF
- Liver function test
 Imaging Studies
- Chest X-ray MANAGEMENT OF SEPSIS
- X-ray of the abdomen • Resuscitate: ABCs
- Abdominal ultrasonography • Restore tissue perfusion
- Abdominal CT scan • Identify and eradicate source of infection
- Plain radiograph of the extremities
• Assure adequate tissue oxygenation
Procedures • Activated protein C
- Orotracheal intubation • Steroids
- Mechanical ventilation • Glucose control
- Urinary foley catheter • Nutrition
- Cutaneous or soft tissue drainage
- Lumbar puncture
- Intravenous access for CVP

SEPTIC SHOCK ALGORITHM EXAMPLE

Consider introducing activated

protein C for 96h if no risk of
bleeding and no clinical Beyond ICU
improvement Rehabilitation
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
Page4