Veterinary Clinical Medicine-I (General and Systemic)

FEVER

• Fever (also known as pyrexia or controlled hyperthermia) is a common medical sign characterized by an elevation of temperature above the normal range due to an increase in the body temperature regulatory set-point.This increase in set-point triggers increased muscle tone and shivering.
• As an animal's temperature increases there is generally a feeling of cold despite an increasing body temperature.
• Once the new temperature is reached there is a feeling of warmth.
• A fever is one of the body's immune responses which attempts to neutralize a bacterial or viral infection.
• A fever can be caused by many different conditions ranging from benign to potentially serious.
• With the exception of very high temperatures, treatment to reduce fever is often not necessary; however, antipyretic medications can be effective at lowering the temperature, and this may improve the affected person's comfort.
• Fever differs from uncontrolled hyperthermia, usually just referred to as hyperthermia, in that hyperthermia is an increase in body temperature over the body's thermoregulatory set-point, due to excessive heat production and/or insufficient thermoregulation.

Classification/Types of Fever

• Fever continues - A
• Fever continues to abrupt onset and remission - B
• Fever remittent - C
• Intermittent fever - D
• Undulant fever - E
• Relapsing fever - F

Hyperpyrexia

• Hyperpyrexia is a fever with an extreme elevation of body temperature greater than or equal to 41.5 °C (106.7 °F).[12] Such a high temperature is considered a veterinary medical emergency as it may indicate a serious underlying condition or lead to significant side effects.
• The most common cause is a intracranial hemorrhage. Other possible causes include sepsis,malignant syndrome, drug effects, serotonin syndrome, and thyroid storm.
• Infections are the most common cause of fevers as the temperature rises other causes become more common.
• Hyperpyrexia differs from hyperthermia in that in hyperpyrexia the body's temperature regulation mechanism sets the body temperature above the normal temperature, then generates heat to achieve this temperature, while in hyperthermia the body temperature rises above its set point.

Pathophysiology

• Temperature is ultimately regulated in the hypothalamus. A trigger of the fever, called a pyrogen, causes a release of prostaglandin E2 (PGE2). PGE2 then in turn acts on the hypothalamus, which generates a systemic response back to the rest of the body, causing heat-creating effects to match a new temperature level.
• In many respects, the hypothalamus works like a thermostat.When the set point is raised, the body increases its temperature through both active generation of heat and retaining heat. Vasoconstriction both reduces heat loss through the skin and causes the person to feel cold.
• The liver produces extra heat. If these measures are insufficient to make the blood temperature in the brain match the new setting in the hypothalamus, then shivering begins, to use muscle movements to produce more heat.
• When the fever stops, and the hypothalamic setting is set lower, the reverse of these processes (vasodilation, end of shivering and nonshivering heat production) and sweating are used to cool the body to the new, lower setting.
• This contrasts with hyperthermia, in which the normal setting remains, and the body overheats through undesirable retention of excess heat or over-production of heat.Hyperthermia is usually the result of an excessively hot environment (heat stroke) or an adverse reaction to drugs.
• Fever can be differentiated from hyperthermia by the circumstances surrounding it and its response to anti-pyretic medications.

Pyrogens

• A pyrogen is a substance that induces fever. These can be either internal (endogenous) or external (exogenous) to the body.
• The bacterial substance lipopolysaccharide (LPS), present in the cell wall of some bacteria, is an example of an exogenous pyrogen.
• Pyrogenicity can vary, as in extreme examples some bacterial pyrogens known as superantigens can cause rapid and dangerous fevers.
• Depyrogenation may be achieved through filtration, distillation, chromatography, or inactivation.

Endogenous Pyrogens

• Cytokines (especially interleukin 1) are a part of the innate immune system, are produced by phagocytic cells, and cause the increase in the thermoregulatory set-point in the hypothalamus. Other examples of endogenous pyrogens are interleukin 6 (IL-6), and tumor necrosis factor-alpha.
• These cytokine factors are released into general circulation where they migrate to the circumventricular organs of the brain due to easier absorption caused by the blood-brain barrier's reduced filtration action there. The cytokine factors then bind with endothelial receptors on vessel walls, or interact with local microglial cells. When these cytokine factors bind, the arachidonic acid pathway is then activated.

Exogenous Pyrogens

• One model for the mechanism of fever caused by exogenous pyrogens includes LPS, which is a cell wall component of gram-negative bacteria.
• An immunological protein called lipopolysaccharide-binding protein (LBP) binds to LPS.
• The LBP–LPS complex then binds to the CD14 receptor of a nearby macrophage.
• This binding results in the synthesis and release of various endogenous cytokine factors, such as interleukin 1 (IL-1), interleukin 6 (IL-6), and the tumor necrosis factor-alpha.
• In other words, exogenous factors cause release of endogenous factors, which, in turn, activate the arachidonic acid pathway.

PGE2 release

• PGE2 release comes from the arachidonic acid pathway.
• This pathway (as it relates to fever), is mediated by the enzymes phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and prostaglandin E2 synthase. These enzymes ultimately mediate the synthesis and release of PGE2.
• PGE2 is the ultimate mediator of the febrile response. The set-point temperature of the body will remain elevated until PGE2 is no longer present. PGE2 acts on neurons in the preoptic area (POA) through the prostaglandin E receptor 3 (EP3).
• EP3-expressing neurons in the POA innervate the dorsomedial hypothalamus (DMH), the rostral raphe pallidus nucleus in the medulla oblongata (rRPa) and the paraventricular nucleus (PVN) of the hypothalamus .
• Fever signals sent to the DMH and rRPa lead to stimulation of the sympathetic output system, which evokes non-shivering thermogenesis to produce body heat and skin vasoconstriction to decrease heat loss from the body surface.
• It is presumed that the innervation from the POA to the PVN mediates the neuroendocrine effects of fever through the pathway involving pituitary gland and various endocrine organs.

Hypothalamus

• The brain ultimately orchestrates heat effector mechanisms via the autonomic nervous system. These may be:
• Increased heat production by
  • Increased muscle tone, shivering and hormones like epinephrine.
  • Prevention of heat loss, such as vasoconstriction.
• The autonomic nervous system may also activate brown adipose tissue to produce heat (non-exercise-associated thermogenesis, also known as non-shivering thermogenesis), but this seems mostly important for babies.
• Increased heart rate and vasoconstriction contribute to increased blood pressure in fever.