FEVER

Dr. Bernardo Dmaso Mata

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Body temperature reflects the difference between heat
production and heat loss and varies with exercise and
extremes of environmental temperature.
Properly protected, the body can function in
environmental conditions that range from 50C (58F)
to +50C (+122F).
Individual body cells, however, cannot tolerate such a
wide range of temperatures: at 1C (+30F) ice
crystals form, and at +45C (+113F), cell proteins
coagulate.
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THERMOREGULATION
Core body temperature is a reflection of the balance between
heat gain and heat loss by the body. Metabolic processes
produce heat, which must be dissipated.
The hypothalamus is the thermal control center for the body,
receives information from peripheral and central
thermoreceptors, and compares that information with its
temperature set point.
Heat loss occurs through transfer of body core heat to the
surface through the circulation. Heat is lost from the skin
through radiation, conduction, convection, and evaporation.
An increase in core temperature is effected by
vasoconstriction and shivering, a decrease in temperature by
vasodilation and sweating.
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Fever represents an increase in body temperature that
results from a cytokine-induced increase in the set-point of
the thermostatic center in the hypothalamus.
Fever is a nonspecific response that is mediated by
endogenous pyrogens released from host cells in response to
infectious or noninfectious disorders.
The development of fever involves a prodrome, a chill during
which the temperature rises until it reaches the new
hypothalamic set-point, a flush during which the skin vessels
dilate and the temperature begins to fall, and a period of
defervescence that is marked by sweating.
Fever is resolved when the condition causing the increase in
the set-point of the thermostatic center in the hypothalamus
is resolved.
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Core body temperature is normally maintained within a range
of 36.0C to 37.5C (97.0F to 99.5F).
Core body and skin temperature are sensed and integrated by
thermoregulatory regions in the hypothalamus and other brain
structures that function to modify heat production and heat
loss as a means of regulating body temperature.
Most of the bodys heat is produced by metabolic processes
that occur within deeper core structures (i.e., muscles and
viscera) of the body.
The sympathetic neurotransmitters (epinephrine and
norepinephrine) and thyroid hormone act at the cellular level
to shift body metabolism to heat production, whereas shivering
and chattering of the teeth use the heat liberated from
involuntary muscle movements to increase body temperature.
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Most of the bodys heat losses occur at the skin
surface as heat from the blood moves through the skin
and from there into the surrounding environment.
Heat is lost from the skin through radiation,
conduction, convection, and evaporation of
perspiration and sweat.
Contraction of the pilomotor muscles of the skin aids
in heat conservation by reducing the surface area
available for heat loss.
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Mechanisms
Fever, or pyrexia, describes an elevation in body
temperature that is caused by an upward
displacement of the thermostatic set-point of the
hypothalamic thermoregulatory center.
Many proteins, breakdown products of proteins, and
certain other substances released from bacterial cell
membranes can cause a change in the set-point to
rise.
Fever is resolved or broken when the condition that
caused the increase in the set-point is removed.
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Mechanisms
Fevers that are regulated by the hypothalamus usually
do not rise above 41C (105.8F), suggesting a built-in
thermostatic safety mechanism.
Temperatures above that level are usually the result of
superimposed activity, such as convulsions,
hyperthermic states, or direct impairment of the
temperature control center.
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Mechanisms
Pyrogens are exogenous or endogenous substances
that produce fever.
Exogenous pyrogens are derived from outside the
body and include such substances as bacterial
products, bacterial toxins, or whole microorganisms.
Exogenous pyrogens induce host cells to produce
fever-producing mediators called endogenous
pyrogens.
When bacteria or breakdown products of bacteria are
present in blood or tissues, they are engulfed by
phagocytic cells of the immune system.
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Mechanisms
These phagocytic cells digest the bacterial products
and then release pyrogenic cytokines, principally
interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor
necrosis factor- (TNF-), into the bloodstream for
transport to the hypothalamus, where they exert their
action.
Prostaglandin E2 (PGE2), which is a metabolite of
arachidonic acid (an intramembrane fatty acid), is
considered to be the final fever mediator in the
hypothalamus, induced by these cytokines.
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Mechanisms
PGE2 binds to receptors in the hypothalamus to
induce changes in its set-point through the second
messenger cyclic adenosine monophosphate (cAMP).
In response to the increase in its thermostatic set-
point, the hypothalamus initiates shivering and
vasoconstriction that raise the bodys core
temperature to the new set-point, and fever is
established.
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Mechanisms
Although the central role of PGE2 in raising the set-
point of the hypothalamic thermoregulatory center
and producing fever is not questioned, recent research
suggests that the febrile response to invading gram-
negative bacteria and their products (mainly endotoxic
lipopolysaccharides) is mediated by peripherally
rather than centrally produced PGE2.
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Mechanisms
These pathogens are thought to activate the
alternative pathway of the complement system, which
in turn stimulates Kupffer cells (i.e., phagocytic cells
found on luminal surface of hepatic sinusoids) in the
liver to produce an almost instantaneous release of
PGE2.
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Mechanisms
The PGE2 produced by the Kupffer cells is thought to
cause an immediate rise in temperature by activating
vagal afferents in the liver that project to the
hypothalamus or by being carried directly to the
hypothalamus by the circulation.
The pyrogenic cytokines (IL-1, IL-2, TNF-) are
produced later and contribute to the continued rise in
temperature.
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Mechanisms
In addition to their fever-producing actions, the
endogenous pyrogens mediate a number of other
responses.
For example, IL-1 and TNF- are inflammatory
mediators that produce other signs of inflammation
such as leukocytosis, anorexia, and malaise.
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Mechanisms
Many noninfectious disorders, such as myocardial
infarction, pulmonary emboli, and neoplasms, produce
fever. In these conditions, the injured or abnormal
cells incite the production of endogenous pyrogens.
For example, trauma and surgery can be associated
with up to 3 days of fever.
Some malignant cells, such as those of leukemia and
Hodgkin disease, secrete chemical mediators that
function as endogenous pyrogens.
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Mechanisms
A fever that has its origin in the central nervous
system is sometimes referred to as a neurogenic
fever.
It usually is caused by damage to the hypothalamus
due to central nervous system trauma, intracerebral
bleeding, or an increase in intracranial pressure.
Neurogenic fevers are characterized by a high
temperature that is resistant to antipyretic therapy
and is not associated with sweating.
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Fever and hyperthermia refer to an increase in body
temperature outside the normal range.
True fever is a disorder of thermoregulation in which
there is an upward displacement of the set-point for
temperature control.
In hyperthermia, the set-point is unchanged, but the
challenge to temperature regulation exceeds the
thermoregulatory centers ability to control body
temperature.
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Fever can be caused by a number of factors, including
microorganisms, trauma, and drugs or chemicals, all
of which incite the release of endogenous pyrogens.
The reactions that occur during fever consist of four
stages: a prodrome, a chill, a flush, and
defervescence.
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A fever can follow an intermittent, remittent,
sustained, or recurrent pattern.
The manifestations of fever are largely related to
dehydration and an increased metabolic rate.
Even a low-grade fever in high-risk infants or in the
elderly can indicate serious infection.
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The treatment of fever focuses on modifying the
external environment as a means of increasing heat
transfer to the external environment; supporting the
hypermetabolic state that accompanies fever;
protecting vulnerable body tissues; and treating the
infection or condition causing the fever.
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Hyperthermia, which varies in severity based on the
degree of core temperature elevation and the severity
of cardiovascular and nervous system involvement,
includes heat cramps, heat exhaustion, and
heatstroke.
Among the factors that contribute to the development
of hyperthermia are prolonged muscular exertion in a
hot environment, disorders that compromise heat
dissipation, and hypersensitivity drug reactions.
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Malignant hyperthermia is an autosomal dominant
disorder that can produce a severe and potentially
fatal increase in body temperature.
The condition commonly is triggered by general
anesthetic agents and muscle relaxants used during
surgery.
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The neuroleptic malignant syndrome is associated
with neuroleptic drug therapy and is thought to result
from alterations in the function of the
thermoregulatory center or from uncontrolled muscle
contraction.
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