FEVER

Med. Bernardo Dámaso Mata

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 −50°C (−58°F) to +50°C (+122°F).

Individual body cells, however, cannot tolerate such a wide range of temperatures: at −1°C (+30°F) ice crystals form, and at +45°C (+113°F), 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 36.0°C to 37.5°C (97.0°F to 99.5°F).

• 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 body’s 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 body’s 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 41°C (105.8°F), 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-α (TNF-α), 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 body’s 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-α) 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-α 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 center’s 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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