Septic shock is a medical condition as a result of severe infection and sepsis,

though the microbe may be systemic or localized to a particular site. It can

cause multiple organ dysfunction syndrome (formerly known as multiple
organ failure) and death. Its most common victims are children,
immunocompromised individuals, and the elderly, as their immune systems
cannot deal with the infection as effectively as those of healthy adults.
Frequently, patients suffering from septic shock are cared for in intensive
care units. The mortality rate from septic shock is approximately 2550%.

Definition
In humans, septic shock has a specific definition requiring several conditions
to be met for diagnosis:

Traditionally, SIRS (systemic inflammatory response syndrome) must first be

diagnosed by finding at least any two of the following:
Tachypnea (high respiratory rate) > 20 breaths per minute, or on blood gas,
a PCO2 less than 32 mmHg signifying hyperventilation.
White blood cell count either significantly low, < 4000 cells/mm3 or elevated
> 12000 cells/mm3.
Heart rate > 90 beats per minute
Temperature: Fever > 38.0 C (100.4 F) or hypothermia < 36.0 C (96.8 F)
However, according to current guidelines, all that is required are 'systemic
manifestations of infection,' broadening the definition beyond the above four.
Second, there must be sepsis and not an alternative form cause of SIRS.
Sepsis requires evidence of infection, which may include positive blood
culture, signs of pneumonia on chest x-ray, or other radiologic or laboratory
evidence of infection.
Third, signs of end-organ dysfunction are required such as renal failure, liver
dysfunction, changes in mental status, or elevated serum lactate.

Finally, septic shock is diagnosed if there is refractory hypotension (low blood

pressure that does not respond to treatment). This signifies that intravenous
fluid administration alone is insufficient to maintain a patient's blood
pressure from becoming hypotensive.
Types
A subclass of distributive shock, septic shock refers specifically to decreased
tissue perfusion resulting in ischemia and organ dysfunction. Cytokines
released in a large scale inflammatory response results in massive
vasodilation, increased capillary permeability, decreased systemic vascular
resistance, and hypotension. Hypotension reduces tissue perfusion pressure
causing tissue hypoxia. Finally, in an attempt to offset decreased blood
pressure, ventricular dilatation and myocardial dysfunction will occur.

Causes
When bacteria or viruses are present in the bloodstream, the condition is
known as bacteremia or viremia. Sepsis is a constellation of symptoms
secondary to infection that manifest as disruptions in heart rate, respiratory
rate, temperature and WBC. If sepsis worsens to the point of end-organ
dysfunction (renal failure, liver dysfunction, altered mental status, or heart
damage), then the condition is called severe sepsis. Once severe sepsis
worsens to the point where blood pressure can no longer be maintained with
intravenous fluids alone, then the criteria have been met for septic shock.
The precipitating infections which may lead to septic shock if severe enough
include, but are not limited to, appendicitis, pneumonia, bacteremia,
diverticulitis, pyelonephritis, meningitis, pancreatitis, and necrotizing
fasciitis.

Pathophysiology
Most cases of septic shock are caused by Gram-positive bacteria, followed by
endotoxin-producing Gram-negative bacteria. Endotoxins are bacterial
membrane lipopolysaccharides (LPS) consisting of a toxic fatty acid (lipid A)
core common to all Gram-negative bacteria, and a complex polysaccharide
coat (including O antigen) unique for each species. Analogous molecules in
the walls of Gram-positive bacteria and fungi can also elicit septic shock. In
Gram-negative sepsis, free LPS attaches to a circulating LPS-binding protein,

and the complex then binds to a specific receptor (CD14) on monocytes,

macrophages, and neutrophils. Engagement of CD14 (even at doses as
minute as 10 pg/mL) results in intracellular signaling via an associated 'Tolllike receptor' protein 4 (TLR-4), resulting in profound activation of
mononuclear cells and production of potent effector cytokines such as IL-1,
IL-6, and TNF-. TLR-mediated activation helps to trigger the innate immune
system to efficiently eradicate invading microbes, but the cytokines they
produce also act on endothelial cells and have a variety of effects, including
reduced synthesis of anticoagulation factors such as tissue factor pathway
inhibitor and thrombomodulin. The effects of the cytokines may be amplified
by TLR-4 engagement on endothelial cells.

At high levels of LPS, the syndrome of septic shock supervenes; the same
cytokine and secondary mediators, now at high levels, result in systemic
vasodilation (hypotension), diminished myocardial contractility, widespread
endothelial injury and activation, causing systemic leukocyte adhesion and
diffuse alveolar capillary damage in the lung activation of the coagulation
system, culminating in disseminated intravascular coagulation (DIC). The
hypoperfusion resulting from the combined effects of widespread
vasodilation, myocardial pump failure, and DIC causes multiorgan system
failure that affects the liver, kidneys, and central nervous system, among
others. Severe damage to liver ultrastructure has been recently noticed by
treatment with cell-free toxins of Salmonella. Unless the underlying infection
(and LPS overload) is rapidly brought under control, the patient usually dies.

Treatment
Treatment primarily consists of the following.

Volume resuscitation
Early antibiotic administration
Early goal directed therapy
Rapid source identification and control.
Support of major organ dysfunction.

Sequestration of lipopolysaccharides.
Among the choices for vasopressors, norepinephrine is superior to dopamine
in septic shock. Both however are still listed as first line in guidelines.

Antimediator agents may be of some limited use in severe clinical situations

however are controversial:

Low dose steroids (hydrocortisone) for 5 7 days led to improved outcomes.

Recombinant activated protein C (drotrecogin alpha) in a 2011 Cochrane
review was found not to decrease mortality and thus was not recommended
for use. Other reviews however comment that it may be effective in those
with very severe disease. The first and only activated protein C drug,
drotrecogin alfa (Xigris), was voluntarily withdrawn in October 2011 after it
failed to show a benefit in patients with septic shock, including the more
severe disease subgroups.
A technique that has shown success and is currently used in Japan, if not
elsewhere, involves sequestering the lipopolysacharides that effectively
cause septic shock. The antibiotic toraymyxin coincidentally does this, but is
also too toxic to be administered. The Japanese technique binds this
toraymixin to an immobile material like polystyrene, and pass the blood over
it, but this isn't always practical. Recent peer-reviewed research has found a
substance derived from the very same spermine found in semen, to bind to
lipopolysaccharids which, so far, seems to be non-toxic as well.

Epidemiology
Sepsis has a worldwide incidence of more than 20 million cases a year, with
mortality due to septic shock reaching up to 50 percent even in industrialized
countries.

According to the US CDC, septic shock is the 13th leading cause of death in
the United States, and the #1 cause of deaths in intensive care units. There
has been an increase in the rate of septic shock deaths in recent decades,

which is attributed to an increase in invasive medical devices and

procedures, increases in immunocompromised patients, and an overall
increase in elderly patients. Tertiary care centers (such as hospice care
facilities) have 2-4 times the rate of bacteremia than primary care centers,
75% of which are nosocomial infections.

The process of infection by bacteria or fungi can result in systemic signs and
symptoms that are variously described. Approximately 70% of septic shock
cases were once traceable to Gram staining gram-negative bacilli that
produce endotoxins; however, with the emergence of MRSA and the
increased use of arterial and venous catheters, Gram-positive cocci are
implicated approximately as commonly as bacilli. In rough order of increasing
severity, these are bacteremia or fungemic; septicemia; sepsis, severe sepsis
or sepsis syndrome; septic shock; refractory septic shock; multiple organ
dysfunction syndrome, and death.

35% of septic shock cases derive from urinary tract infections, 15% from the
respiratory tract, 15% from skin catheters (such as IVs); over 30% of all
cases are idiopathic in origin.

The mortality rate from sepsis is approximately 40% in adults, and 25% in
children, and is significantly greater when left untreated for more than 7
days.