FEVER AND HYPERTHERMIA 1

FEVER AND HYPERTHERMIA

Body temperature is controlled by the hypothalamus. Neurons in both the preoptic anterior hypothalamus and the posterior hypothalamus receive two kinds of signals: one from peripheral nerves that reflect warmth/cold receptors and the other from the temperature of the blood bathing the region. These two types of signals are integrated by the thermoregulatory center of the hypothalamus to maintain normal temperature. In a neutral environment, the metabolic rate of humans consistently produces more heat than is necessary to maintain the core body temperature at 37°C. Therefore, the hypothalamus controls temperature by mechanisms of heat loss.

A normal body temperature is ordinarily maintained, despite environmental variations, because the hypothalamic thermoregulatory center balances the excess heat production derived from metabolic activity in muscle and the liver with heat dissipation from the skin and lungs. According to recent studies of healthy individuals 18 to 40 years of age, the mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F), with low levels at 6 A.M. and higher levels at 4 to 6 P.M. The maximum normal oral temperature is 37.2°C (98.9°F) at 6 A.M. and 37.7°C (99.9°F) at 4 P.M.; these values define the 99th percentile for healthy individuals. In light of these studies, an A.M. temperature of >37.2°C (98.9°F) or a P.M. temperature of >37.7°C (99.9°F) would define a fever. The normal daily temperature variation is typically 0.5°C (0.9°F). However, in some individuals recovering from a febrile illness, this daily variation can be as great as 1.0°C. During a febrile illness, diurnal variations are usually maintained but at higher levels. Daily temperature swings do not occur in patients with hyperthermia (see below). Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings. The lower oral readings are probably attributable to mouth breathing, which is a particularly important factor in patients with respiratory infections and rapid breathing. Lower esophageal temperatures closely reflect core temperature. Tympanic membrane (TM) thermometers measure radiant heat energy from the tympanic membrane and nearby ear canal and display that absolute value (unadjusted mode) or a value automatically calculated from the absolute reading on the basis of nomograms relating the radiant temperature measured to actual core temperatures obtained in clinical studies (adjusted mode). These measurements, although convenient, may be more variable than directly determined oral or rectal values. Studies in adults show that readings are lower with unadjusted-mode than with adjusted-mode TM thermometers and that unadjusted-mode TM values are 0.8°C (1.6°F) lower than rectal temperatures.

In women who menstruate, the A.M. temperature is generally lower in the 2 weeks before ovulation; it then rises by about 0.6°C (1°F) with ovulation and remains at that level until menses occur. Seasonal variation in body temperature has been described but may reflect a metabolic change and is not common. Body temperature is elevated in the postprandial state, but this elevation does not represent fever. Pregnancy and endocrinologic dysfunction also affect body temperature. The daily temperature variation appears to be fixed in early childhood; in contrast, elderly individuals can exhibit a reduced ability to develop fever, with only a modest fever even in severe infections.

FEVER VERSUS HYPERTHERMIA

FEVER

Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point¾for example, from 37°C to 39°C. This shift of the set point from "normothermic" to febrile levels very much resembles the resetting of the home thermostat to a higher level in order to raise the ambient temperature in a room. Once the hypothalamic set point is raised, neurons in the vasomotor center are activated and vasoconstriction commences. The individual first notices vasoconstriction in the hands and feet. Shunting of blood away from the periphery to the internal organs essentially decreases heat loss from the skin, and the person feels cold. For most fevers, body temperature increases by 1 to 2°C. Shivering, which increases heat production from the muscles, may begin at this time; however, shivering is not required if heat conservation mechanisms raise blood temperature sufficiently. Heat production from the liver also increases. In humans, behavioral instincts (e.g., putting on more clothing or bedding) lead to a reduction of exposed surfaces, which helps raise body temperature.

The processes of heat conservation (vasoconstriction) and heat production (shivering and increased metabolic activity) continue until the temperature of the blood bathing the hypothalamic neurons matches the new thermostat setting. Once that point is reached, the hypothalamus maintains the temperature at the febrile level by the same mechanisms of heat balance that are operative in the afebrile state. When the hypothalamic set point is again reset downward (due to either a reduction in the concentration of pyrogens or the use of antipyretics), the processes of heat loss through vasodilation and sweating are initiated. Behavioral changes triggered at this time include the removal of insulating clothing or bedding. Loss of heat by sweating and vasodilation continues until the blood temperature at the hypothalamic level matches the lower setting.

A fever of >41.5°C (106.7°F) is called hyperpyrexia. This extraordinarily high fever can develop in patients with severe infections but most commonly occurs in patients with central nervous system hemorrhages. In the preantibiotic era, fever due to a variety of infectious diseases rarely exceeded 106°F, and there has been speculation that this natural "thermal ceiling" is mediated by neuropeptides functioning as central antipyretics.

In some rare cases, the hypothalamic set point is elevated as a result of local trauma, hemorrhage, tumor, or intrinsic hypothalamic malfunction. The term hypothalamic fever is sometimes used to describe elevated temperature caused by abnormal hypothalamic function. However, most patients with hypothalamic damage have subnormal, not supranormal, body temperatures. These patients do not respond properly to mild environmental temperature changes. For example, when exposed to only mildly cold conditions, their core temperature falls quickly rather than over the normal period of a few hours. In the very few patients in whom elevated core temperature is suspected to be due to hypothalamic damage, diagnosis depends on the demonstration of other abnormalities in hypothalamic function, such as the production of hypothalamic releasing factors, abnormal response to cold, and absence of circadian temperature and hormonal rhythms.

HYPERTHERMIA

Hyperthermia is characterized by an unchanged (normothermic) setting of the thermoregulatory center in conjunction with an uncontrolled increase in body temperature that exceeds the body's ability to lose heat. Exogenous heat exposure and endogenous heat production are two mechanisms by which hyperthermia can result in dangerously high internal temperatures. Excessive heat production can easily cause hyperthermia despite physiologic and behavioral control of body temperature. For example, over-insulating clothing can result in an elevated core temperature, and work or exercise in hot environments can produce heat faster than peripheral mechanisms can lose it.

Although most patients with elevated body temperature have fever, there are a few circumstances in which elevated temperature represents not fever but hyperthermia. Heat stroke, caused by thermoregulatory failure in association with a warm environment, may be categorized as exertional or nonexertional. Exertional heat stroke typically occurs in younger individuals exercising at ambient temperatures and/or humidities that are higher than normal. Even in normal individuals, dehydration or the use of common medications (e.g., over-the-counter antihistamines with anticholinergic side effects) may help to precipitate exertional heat stroke. Nonexertional or classic heat stroke typically occurs in elderly individuals, particularly during heat waves. For example, in Chicago in July 1995, 465 deaths were certified as heat related. The elderly, the bedridden, persons taking anticholinergic or antiparkinsonian drugs or diuretics, and individuals confined to poorly ventilated and non-air-conditioned environments are most susceptible.

Drug-induced hyperthermia has become increasingly common as a result of the increased use of prescription psychotropic drugs and illicit drugs. Drug-induced hyperthermia may be caused by monoamine oxidase inhibitors, tricyclic antidepressants, and amphetamines and by the illicit use of phencyclidine, lysergic acid diethylamide (LSD), or cocaine.

Malignant hyperthermia occurs in individuals with an inherited abnormality of skeletal-muscle sarcoplasmic reticulum that causes a rapid increase in intracellular calcium levels in response to halothane and other inhalational anesthetics or to succinylcholine. Elevated temperature, increased muscle metabolism, rigidity, rhabdomyolysis, acidosis, and cardiovascular instability develop rapidly. This condition is often fatal. The neuroleptic malignant syndrome can occur with phenothiazines and other drugs such as haloperidol and is characterized by muscle rigidity, autonomic dysregulation, and hyperthermia. This disorder appears to be caused by the inhibition of central dopamine receptors in the hypothalamus, which results in increased heat generation and decreased heat dissipation. Thyrotoxicosis and pheochromocytoma can also cause increased thermogenesis.

It is important to distinguish between fever and hyperthermia since hyperthermia can be rapidly fatal and characteristically does not respond to antipyretics. However, there is no rapid way to make this distinction. Hyperthermia is often diagnosed on the basis of the events immediately preceding the elevation of core temperature¾e.g., heat exposure or treatment with drugs that interfere with thermoregulation. However, in addition to the clinical history of the patient, the physical aspects of some forms of hyperthermia may alert the clinician. For example, in patients with heat stroke syndromes and in those taking drugs that block sweating, the skin is hot but dry. Moreover, antipyretics do not reduce the elevated temperature in hyperthermia, whereas in fever¾and even in hyperpyrexia¾adequate doses of either aspirin or acetaminophen usually result in some decrease in body temperature.

PYROGENS

The term pyrogen is used to describe any substance that causes fever. Exogenous pyrogens are derived from outside the patient; most are microbial products, microbial toxins, or whole microorganisms. The classic example of an exogenous pyrogen is the lipopolysaccharide endotoxin produced by all gram-negative bacteria. Endotoxins are potent not only as pyrogens but also as inducers of various pathologic changes in gram-negative infections. Another group of potent bacterial pyrogens is produced by gram-positive organisms and includes the enterotoxins of Staphylococcus aureus and the group A and B streptococcal toxins, also called superantigens. One staphylococcal toxin of clinical importance is the toxic shock syndrome toxin associated with isolates of S. aureus from patients with toxic shock syndrome. Like the endotoxins of gram-negative bacteria, the toxins produced by staphylococci and streptococci cause fever in experimental animals when injected intravenously at concentrations of <1 ug/kg of body weight. Endotoxin is a highly pyrogenic molecule in humans: a dose of 2 to 3 ng/kg produces fever and generalized symptoms of malaise in volunteers.

PYROGENIC CYTOKINES

Cytokines are small proteins (molecular mass, 10,000 to 20,000 Da) that regulate immune, inflammatory, and hematopoietic processes. For example, stimulation of lymphocyte proliferation during an immune response to vaccination is the result of the cytokines interleukin (IL) 2, IL-4, and IL-6. Another cytokine, granulocyte colony-stimulating factor, stimulates granulocytopoiesis in the bone marrow. Some cytokines cause fever and hence are called pyrogenic cytokines. From a historic point of view, the field of cytokine biology began in the 1940s with laboratory investigations into fever induction by products of activated leukocytes. These fever-producing molecules were called endogenous pyrogens. When endogenous pyrogens were purified from activated leukocytes, they were shown to possess various biologic activities, which are now recognized as the properties of the various cytokines.

The known pyrogenic cytokines include IL-1, IL-6, tumor necrosis factor (TNF), ciliary neurotropic factor (CNTF), and interferon (IFN) a. Others probably exist. Each cytokine is encoded by a separate gene, and each pyrogenic cytokine has been shown to cause fever in laboratory animals and in humans. When injected into humans, IL-1, IL-6, and TNF produce fever at low doses (10 to 100 ng/kg).

The synthesis and release of endogenous pyrogenic cytokines are induced by a wide spectrum of exogenous pyrogens, most of which have recognizable bacterial or fungal sources. Viruses also induce pyrogenic cytokines by infecting cells. However, in the absence of microbial infection, inflammation, trauma, tissue necrosis, or antigen-antibody complexes can induce the production of IL-1, TNF, and/or IL-6, which¾individually or in combination¾trigger the hypothalamus to raise the set point to febrile levels. The cellular sources of pyrogenic cytokines are primarily monocytes, neutrophils, and lymphocytes, although many other types of cells can synthesize these molecules when stimulated.

ELEVATION OF THE HYPOTHALAMIC SET POINT BY CYTOKINES

During fever, levels of prostaglandin E2 (PGE2) are elevated in hypothalamic tissue and the third cerebral ventricle. The concentrations of PGE2 are highest near the circumventricular vascular organs (organum vasculosum of lamina terminalis)¾networks of enlarged capillaries surrounding the hypothalamic regulatory centers. Destruction of these organs reduces the ability of pyrogens to produce fever. Most studies in animals have failed to show, however, that pyrogenic cytokines pass from the circulation into the brain itself. Thus, it appears that both exogenous and endogenous pyrogens interact with the endothelium of these capillaries and that this interaction is the first step in initiating fever¾i.e., in raising the set point to febrile levels.

The key events in the production of fever are illustrated in . As has been mentioned, several cell types can produce pyrogenic cytokines. Pyrogenic cytokines such as IL-1, IL-6, and TNF are released from the cells and enter the systemic circulation. Although the systemic effects of these circulating cytokines lead to fever by inducing the synthesis of PGE2, they also induce PGE2 in peripheral tissues. The increase in PGE2 in the periphery accounts for the nonspecific myalgias and arthralgias that often accompany fever. However, it is the induction of PGE2 in the brain that starts the process of raising the hypothalamic set point for core temperature.

There are four receptors for PGE2, and each signals the cell in different ways. Of the four receptors, the third (EP-3) is essential for fever: when the gene for this receptor is deleted in mice, no fever follows the injection of IL-1 or endotoxin. Deletion of the other PGE2 receptor genes leaves the fever mechanism intact. Although PGE2 is essential for fever, it is not a neurotransmitter. Rather, the release of PGE2 from the brain side of the hypothalamic endothelium triggers the PGE2 receptor on glial cells, and this stimulation results in the rapid release of cyclic adenosine 5¢-monophosphate (cyclic AMP), which is a neurotransmitter. As shown in, the release of cyclic AMP from the glial cells activates neuronal endings from the thermoregulatory center that extend into the area. The elevation of cyclic AMP is thought to account for changes in the hypothalamic set point either directly or indirectly by inducing the release of monoamine neurotransmitters. Since receptors for endotoxin are in many ways similar to IL-1 receptors, the activation of endotoxin receptors on the hypothalamic endothelium also results in PGE2 production and fever.

PRODUCTION OF CYTOKINES IN THE CENTRAL NERVOUS SYSTEM

Several viral diseases produce active infection in the brain. Glial and possibly neuronal cells synthesize IL-1, TNF, and IL-6. CNTF is also synthesized by neural as well as neuronal cells. What role in the production of fever is played by these cytokines produced in the brain itself? In experimental animals, the concentrations of cytokine required to cause fever are several orders of magnitude lower with direct injection into the brain than with intravenous injection. Therefore, central nervous system production of these cytokines apparently can raise the hypothalamic set point, bypassing the circumventricular organs involved in fever caused by circulating cytokines. Central nervous system cytokines may account for the hyperpyrexia of central nervous system hemorrhage, trauma, or infection.