Dantrolene

Continuing Education

This article has been designated for CE credit. A closed-book, multiple-choice examination follows this article, which tests your knowledge of the following objectives:

1. Identify the physiological causes that lead to temperature elevation.

2. Explain the mechanisms involved in the pathophysiology of fever.

3. Discuss the medical management of fever.

Elevated body temperature in critically ill patients is a long-standing concern for nurses. Studies have shown that 29% to 36% of all hospitalized patients have fever listed as one of their signs and symptoms. (1) Several questions usually arise. Are all elevations in temperature a fever? If this is a fever, when is it severe enough to become a concern? If this is not a fever, what is it? What signs and symptoms give clues to differentiate the possible causes of body temperature elevation?

Temperature homeostasis is controlled by the hypothalamus, which acts as a thermostat that sets the body's target temperature. In fever, this temperature set point is elevated and the body responds by implementing internal heat conservation methods to reach this new temperature. This heat conservation results in an elevation in core body temperature, a process that is metabolically expensive. However, although fever is often given a negative connotation, this response must provide some benefit for the host or it would not have been preserved throughout human evolution. (2)

Many different syndromes can lead to elevation of body temperature. Fever is one cause and is most frequently triggered by infection or inflammation. Other causes of temperature elevation are heat stroke, neuroleptic malignant syndrome, and malignant hyperthermia. These causes differ from fever because the temperature elevation seen with these syndromes is the result of an imbalance between heat production and heat loss rather than a change in hypothalamic set point.

Physiology of Temperature Regulation

Body temperature is controlled by the hypothalamus, which sets the target temperature, or set point, for the body. This set point has diurnal fluctuations with a nadir occurring at 6 AM and a zenith at 6 PM. Although 37[degrees]C is considered normal, each person has his or her own baseline temperature, usually between 36.4[degrees]C and 37.7[degrees]C. Overall, excluding illness and exercise-induced hyperthermia, a person's body temperature varies less than 1[degrees]C during a lifetime. (3)

The hypothalamus receives feedback through 2 different pathways. Peripheral nerves provide 1 pathway by directing cool/warmth sensations back to the brain. The hypothalamus provides another feedback pathway by sensing heat from the surrounding brain tissues. If either of these 2 pathways senses a heat level above the set point, the hypothalamus responds to lower the body temperature by increasing heat loss. This increased heat loss occurs through vasodilatation of cutaneous circulation and increased sweating from sweat glands. If the heat sensed in the periphery and around the hypothalamus is below the set point, the hypothalamus triggers heat conservation through sympathetic activity, leading to decreased heat dissipation. Through these mechanisms, the hypothalamus regulates the balance between heat loss and heat production. (4)

Pathophysiology of Fever

The thermoregulatory center is located in the anterior portion of the hypothalamus. When the vascular bed surrounding the hypothalamus is exposed to certain exogenous pyrogens (bacterial) or endogenous pyrogens (interleukin-1, interleukin-6, tumor necrosis factor), arachidonic acid metabolites are released from the endothelial cells of this vascular network. These metabolites, such as prostaglandin [E.sub.2], cross the blood-brain barrier and diffuse into the thermoregulatory area of the hypothalamus, triggering the cascade of events that ultimately increases the set point. With the higher set point established, the hypothalamus sends sympathetic signals to peripheral blood vessels, causing vasoconstriction and decreased heat loss through the skin. Increased sympathetic activity also initiates piloerection, which thickens the body's insulating shell. If these adjustments do not salvage enough heat to match the new set point, shivering is triggered through the spinal and supraspinal motor system to cause an increase in heat production. The goal of the body is to reach the new set point. (3)

The initiation phase is the period when the body's temperature is increasing but has not reached the set point. Chills, cold skin, and shivering are the primary symptoms indicating the body's attempt to conserve heat. The plateau phase occurs when the actual body temperature matches the set point temperature. At that time, the chills and shivering cease. When the hypothalamus is no longer stimulated by pyrogens, the set point returns to normal. This final phase, called defervescence, is characterized by flushing, diaphoresis, and feeling warm as the body tries to dissipate heat. In some severe states of sepsis, these 3 phases do not occur. In this case, the toxins released by the infection overwhelm the body, causing early vasodilatation, loss of the ability to conserve heat, and initiation of the shock syndrome. (1) The elderly also may lose the ability to generate a fever, possibly because of malnutrition, loss of subcutaneous fat, decreased compensatory peripheral vascular tone, decreased thermal feedback, or impaired shivering. (5)

When fever occurs, many physiological stresses take place. Some of these include increased oxygen consumption as a response to increased cell metabolism, increased heart rate, increased cardiac output, increased leukocyte count, and an increased level of C-reactive protein. Oxygen consumption increases by 13% for every 1[degrees]C increase in body temperature, provided no shivering occurs. If shivering is present, oxygen consumption may increase by 100% to 200%. (1) Some cytokines released during fever states also induce physiological stress. These cytokines can trigger accelerated muscle catabolism by causing weight loss, loss of strength, and negative nitrogen balance. Physiological stress can be manifested by decreased mental acuity, delirium, and seizures, which are more frequent in children. (4)

Results of studies with various animal models suggest that fever has some beneficial effects on the body's response to infection. Heat shock proteins are one of the more recently studied fever-responsive proteins. These proteins are produced during fever states and are critical for cellular survival during stress. Studies suggest that these proteins may have anti-inflammatory effects by decreasing the levels of proinflammatory cytokines. (6) Fever also triggers other beneficial effects, including an increase in the phagocytic and bacteriocidal activity of neutrophils and enhanced cytotoxic effects of lymphocytes. Some bacteria become less virulent and grow slower at the higher temperatures associated with fever. Increased levels of C-reactive protein promote phagocytic adherence to invading organisms, modulate inflammation, and encourage tissue repair. (2)

Differential Diagnosis

When heat production overruns heat dissipation, an elevated temperature results. If this is the result of an adjusted set point in the hypothalamus, fever is the outcome. In contrast, hyperthermia may result from either an increase in the body's heat production or the body's loss of the ability to dissipate heat efficiently. Hyperthermia can present as a symptom of various physiological conditions such as malignant hyperthermia, neuroleptic malignant syndrome, and heat stroke.

Malignant hyperthermia is a rare autosomal dominant disorder affecting the sarcoplasmic reticulum. In unaffected persons, the sarcoplasmic reticulum stores the calcium for the myocyte and is also responsible for the reuptake of calcium to terminate muscle contraction. In persons affected by this genetic defect, signs and symptoms are usually triggered by exposure to inhalational anesthetics or succinylcholine. These medications appear to cause a rapid influx of calcium into the sarcomere of the muscle cell due to the abnormality in the sarcoplasmic reticulum. The increase in intracellular calcium triggers multiple events that lead to production of large quantities of heat. The body is unable to dissipate that amount of heat, and hyperthermia develops. Signs and symptoms appear suddenly, usually starting with ventricular ectopy, rapid respirations, and labile blood pressure. Hyperthermia develops quickly with temperatures increasing 1[degrees]C every 5 minutes and peaking at temperatures of 42[degrees]C to 46[degrees]C. Muscle rigidity usually follows, resulting from the failure of reuptake of calcium by the sarcoplasmic reticulum. Laboratory studies demonstrate severe mixed acidosis, hyperglycemia, hyperkalemia, hypermagnesemia, hyperphosphatemia, and hypercalcemia as early findings. As the syndrome progresses, serum calcium levels decrease and muscle enzyme levels increase. Elevation in creatine kinase level is frequently observed and serves as an indicator of the development of rhabdomyolysis. (7)

Treatment begins by immediate cessation of anesthesia and administration of dantrolene sodium, which is thought to lower the cellular calcium concentration and thus decrease heat production. Supportive care involves intravenous fluids, electrolyte monitoring and management, oxygenation with possible ventilatory support, and physical cooling. Cooling may involve both external cooling, by means of cooling blankets, fans, and sponge baths, and also internal cooling by iced gastric or peritoneal lavages. Antipyretics are ineffective in this situation because the problem resides in the function of the sarcoplasmic reticulum rather than the hypothalamic set point. (4)

Neuroleptic malignant syndrome is another pharmacologically induced hyperthermia. This syndrome is associated most frequently with the use of phenothiazines, tricyclic antidepressants, metoclopramide, fluoxetine, and butyrophenones such as haloperidol. Abnormal inhibition of the central dopamine receptors in the hypothalamus by these drugs appears to lead to autonomic dysregulation. This dysregulation leads to muscle rigidity and heat production. Because these dopamine receptors normally stimulate heat loss, dysfunction then causes vasoconstriction and decreased ability to dissipate heat. The patient usually exhibits change in sensorium, rigidity and involuntary muscle movements, hyperthermia, unstable blood pressures, tachycardia, tachypnea, pallor, diaphoresis, and pulmonary congestion. Dehydration, rhabdomyolysis, and exhaustion are the possible consequences. (7)

Treatment for neuroleptic malignant syndrome is similar to malignant hyperthermia. Determination and cessation of the use of the offending pharmacological agent is imperative. Supportive care is essential in order to decrease the negative consequences. Dantrolene sodium is the drug of choice to decrease muscular heat production by decreasing intracellular calcium in the myocytes. Other medications such as bromocriptine and amantadine may also have some benefit. (7)

Heat stroke can be classified as either classic or exertional. Classic heat stroke usually involves the very young and very old, particularly during heat waves. Many times, these groups are unable to satisfy thirst signals independently or control their environmental temperature. The elderly may be taking diuretics, anticholenergic agents, or antiparkinson medications that put them at risk for dehydration and hyperthermia. As their environmental temperature increases, it becomes more difficult for their normal physical mechanisms to balance normal heat production with heat loss. Sweating is usually absent because of dehydration or the result of medications. On the other hand, exertional heat stroke usually results from strenuous activity, where heat production overwhelms the body's ability to dissipate it. Sweating is a common finding. Athletes and those in the military are more prone to heat stroke because of activity level, but for unknown reasons, this tendency is less common in women. Unlike the classic form, exertional heat stroke is more likely to manifest as lactic acidosis, rhabdomyolysis, hypoglycemia, and acute renal failure. With this young adult age group, if pharmacological agents are involved, they are more likely to be amphetamines or cocaine. Mental status changes, from confusion to coma, are common in both types of heat stroke. Complications for both types include renal failure, hyperkalemia, and shock. Shock usually develops because of peripheral vasodilatation and usually responds to the cooling process. To prevent fluid overload, fluid resuscitation with isotonic sodium chloride solution should be attempted only after cooling is initiated. (7)

To treat heat stroke, first remove the patient from the environment or cease activity. Supportive care is again essential, with the goal being to lower the body temperature. (4) Misting the body with tepid water is just as effective as ice water baths but decreases risk of shivering. Avoiding shivering is important because shivering increases heat production and may lead to seizures. Ice water lavages are not recommended because they may lead to large fluid shifts causing water intoxication and electrolyte abnormalities. This result does not occur in neuroleptic malignant syndrome and malignant hyperthermia because in those cases dehydration is not as large a component as in heat stroke. Even with aggressive treatment, permanent damage to the central nervous system may occur, including dystonia, thermoregulatory dysfunction, and dementia. (7)

Other potential causes of hyperthermia are drug reactions, especially to anti-neoplastics and antibiotics, blood reactions, and endocrine problems such as thyroid storm and pheochromocytoma.

Myths and History of Fever

One of the first known written references to fever was found in Akkadian inscriptions from about the sixth century BC. These appear to have been interpretations of ancient Sumerian hieroglyphics depicting fever. In the fifth century BC, written works of Hippocrates presented thoughts on the pathogenesis of fever. Health, during that time, was described as the delicate balance among the 4 corporeal humors: blood, phlegm, black bile, and yellow bile. An excess of yellow bile was thought to cause fever. The goal was to restore balance among these humors so that health would be restored. Willow bark, a precursor to aspirin, was also mentioned in his writings as a remedy for fever, along with various aches and pains. During the Middle Ages, fevers were thought to be the sign of demonic possession, to be dealt with on the spiritual and ritualistic level. By the 1700s, new information on blood circulation and microbiology brought other hypotheses that fever was caused by fermentation occurring in the blood. (2)

One of the well-known fables of fever, which can be traced back to 1574, is "Feed a cold, starve a fever." John Withals, a lexicographer, printed one of the wives' tales on fever, "fasting is a great remedie [sic] for fever" in one of his books, A Short Dictionary Most Profitable for Young Beginners. The exact statement was first noted in Mark Twain's "The Celebrated Jumping Frog of Calaveras County" in 1865. The original thought to the statement was "If you stuff a cold now, you will have to later starve a fever." The idea was that if an ill person was fed, then more fuel was available for the body to rally a higher fever. (8)

Recently, several studies looked at just that idea, the body's immune response to feeding and starvation. G. R. van den Brink (9) spearheaded a small study in the Netherlands and found that food intake resulted in increased cell-mediated immunity with elevated levels of a cytokine, [gamma]-interferon. This specific cytokine is thought to increase the body's defense against chronic illnesses. When the participants received only liquids, higher concentrations of a cytokine, interleukin-4, were found. This cytokine indicates a stronger humoral immune response, which is associated with antibody production, the front-line defense against acute infections. (9) Further studies are needed on a larger scale to determine the accuracy of these findings.

Medical Management

When elevation of body temperature occurs, the first priority is to determine if the elevation is due to a fever or to hyperthermia. Evaluating signs and symptoms, severity and onset of the temperature elevation, absence of a prodromal period, and the clinical situation in which the patient is found will help in differentiating fever from hyperthermia. If the elevation in temperature is hyperthermia, then prompt action should be taken, as mentioned earlier.

Fever is a sign of an underlying problem. Therefore, the focus must be on determining the original clinical problem so as to relieve that problem. Fever is thought to be a protective response of the body to a clinical problem. Allowing the fever to take its course can help determine the cause. Fever patterns and timing of the fever's development can assist in including or excluding certain clinical problems. Although antipyretics can relieve constitutional symptoms of malaise, headache, and myalgias, these medications can obscure clinical information and mask inflammatory features helpful in determining the cause of the clinical situation. Only if the increase in body temperature is severe (to [greater than or equal to]41[degrees]C) should fever reduction be considered. Exceptions are children with history of febrile seizures, pregnant women, and debilitated patients with impaired cardiac, pulmonary, or cerebral function, owing to their inability to compensate for the increased metabolic demands. (4) Physiological cooling, through cooling blankets or misting, should accompany pharmacological management. Avoidance of bundling the patient in blankets is crucial because this discourages heat dissipation. Awareness of patients' fluid status and the prevention of dehydration are essential. The following is a short summary of the more frequently used antipyretics. Although most of these are over-the-counter medications, nurses should become familiar with the use and the consequences of misuse of these commonly used drugs.

Aspirin blocks the production of prostaglandins and the brain's response to interleukin-1, which is released by macrophages. Blocking the brain's response to interleukin-1 decreases the stimulation of the thermoregulatory center of the hypothalamus and allows down-regulation of the temperature set point. As the set point decreases, the body then triggers vasodilatation to occur. Recommended dosage is 325 mg to 650 mg every 4 hours with maximum 4.0 g a day for an adult. Children younger than 16 years should not take aspirin because of the risk of Reye syndrome, especially after viral infections. (10) Reye syndrome results in brain swelling and massive fatty deposits in the liver.

Ibuprofen also inhibits the synthesis of prostaglandin, causing less stimulation of the set point of temperature in the hypothalamus. A dose of 2.4 g of ibuprofen daily is equivalent to 4.0 g of aspirin daily. The usual dosage of ibuprofen is 200 mg to 400 mg every 4 to 6 hours, with a maximum daily dose of 1.2 g. Because ibuprofen is metabolized in the liver, caution is needed with patients with liver disease. Hemorrhage, acute renal failure, hepatic dysfunction, and angioedema are possible adverse effects of both ibuprofen and aspirin.

In the cerebral cortex, acetaminophen is converted into an active form of cyclooxygenase inhibitor, which has an antipyretic effect. Cyclooxygenase is thought to be responsible for stimulating prostaglandin production. Therefore, inhibiting cyclooxygenase results in a reduction in hypothalamic temperature set point, leading to vasodilatation and sweating. (4) Usual dosage is 325 mg to 650 mg every 4 to 6 hours or 1000 mg 3 to 4 times a day, with a maximum 4.0 g a day for an adult. For infants and children, a reduced dose of 10 to 15 mg/kg every 6 hours is recommended. Hepatotoxicity is a concern, especially at higher doses. Use caution with people with liver disease, alcoholism, and impaired renal function. (10)

Glucocorticoids can also be used to treat fever, functioning by inhibiting prostaglandin synthesis. They have strong immunosuppressive and antiphagocytic properties, however, which limit their use during infectious states. Meperidine, morphine, and chlorpromazine are effective in reducing severe rigors that may accompany fevers. (4)

An elevated body temperature may not always be a fever. Because many syndromes can lead to an elevated body temperature, understanding the pathophysiology of each will provide a framework to guide the diagnosis. With appropriate assessment, accurate differentiation of fever from hyperthermia is possible. Appropriate therapy must be started quickly to address the physical cause of the temperature elevation. Fever is the body's response to infection. Awareness of both the beneficial and injurious effects of fever helps to guide clinicians in the care of patients.

CE Test Instructions

To receive CE credit for this test (ID# CG0205), mark your answers on the form below, complete the enrollment information, and submit it with the $12 processing fee (payable in US funds) to the American Association of Critical-Care Nurses (AACN). Answer forms must be postmarked by February 1, 2007. Within 3 to 4 weeks of AACN receiving your test form, you will receive an AACN CE certificate.

This continuing education program is provided by AACN, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. AACN has been approved as a provider of continuing education by the State Boards of Nursing of Alabama (#ABNP0062), California (01036), Florida (#FBN2464), Iowa (#332), Louisiana (#ABN12), and Nevada. AACN programming meets the standards for most other states requiring mandatory continuing education credit for relicensure.

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CE Test Questions

Fever: Facts, Fiction, Physiology

1. What percentage of hospitalized patients have fever listed as a sign and symptom of their illness?

a. 5% to 8%

b. 10% to 15%

c. 29% to 36%

d. 40% to 45%

2. Which of the following causes of temperature elevation results from a change in hypothalamic set point?

a. Heat stroke

b. Neuroleptic malignant syndrome

c. Malignant hyperthermia

d. Fever

3. What time is the nadir for body temperature?

a. 6 AM

b. 3 AM

c. 3 PM

d. 6 PM

4. What is the range of normal body temperature?

a. 34.4 C to 36.3[degrees]C

b. 35.6 C to 37.0[degrees]C

c. 36.4 C to 37.7[degrees]C

d. 36.7 C to 38.0[degrees]C

5. Where is the thermoregulatory center located?

a. Posterior pituitary

b. Anterior hypothalamus

c. Brainstem

d. Anterior medulla

6. Which phase of fever occurs when the body's temperature is increasing but has not reached the set point?

a. Prefebrile phase

b. Initiation phase

c. Plateau phase

d. Defervescence phase

7. Which phase is characterized by flushing, diaphoresis, and warmth from heat dissipation?

a. Prefebrile phase

b. Initiation phase

c. Plateau phase

d. Defervescence phase

8. Which of the following clinical conditions is not associated with the occurrence of all the temperature phases?

a. Heat stroke

b. Sepsis

c. Meningitis

d. Avian flu

9. How much does oxygen consumption increase for every 1[degrees]C increase in body temperature?

a. 5%

b. 8%

c. 13%

d. 21%

10. How much does shivering increase oxygen consumption?

a. 25%

b. 50%

c. 75%

d. 100%

11. Which of the following is a pharmacologically induced form of hyperthermia?

a. Heat stroke

b. Malignant hyperthermia

c. Neuroleptic malignant syndrome

d. Rhabdomyolysis

12. At what temperature elevation should fever reduction measures be considered?

a. 38[degrees]C

b. 39[degrees]C

c. 40[degrees]C

d. 41[degrees]C

References

1. Henker R, Kramer D. Rogers S. Fever. AACN Clin Issues. 1997;3:351-367.

2. Mackowiak PA. Concepts of fever. Arch Intern Med. 1998;158:1870-1881.

3. Boulant JA. Thermoregulation. In: Mackowiak, PA, ed. Fever: Basic Mechanisms and Management. 2nd ed. New York, NY: Lippincott-Raven Publishers; 1997:35-58.

4. Gelfand JA, Dinarello CA. Fever and hyperthermia. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998:84-89.

5. Bender BS, Scarpace PJ. Fever in the elderly. In: Mackowiak PA, ed. Fever: Basic Mechanisms and Management. 2nd ed. New York, NY: Lippincott-Raven Publishers; 1997:363-381.

6. Ryan M, Levy MM. Clinical review: fever in the intensive care patients. Crit Care. 2003;7:221-225.

7. Knochel JP, Goodman EL. Heat stroke and other forms of hyperthermia. In: Mackowiak PA, ed. Fever: Basic Mechanisms and Management. 2nd ed. New York, NY: Lippincott-Raven Publishers; 1997:437-457.

8. Flexner S, Flexner D. Wise Words and Wives' Tales: The Origins, Meanings and Time-Honored Wisdom of Proverbs and Folk Sayings Olde and New. New York, NY: Avon Books; 1993.

9. van den Brink GR, van den Boogardt DEM, van Deventer SIH, Peppelenbosch MP. Feed a cold, starve a fever? Clin Diagnostic Lab Immunol. 2002;9:182-183.

10. Turkoski BB, Lance BR, Bonfiglio MF. Drug Information Handbook for Advanced Practice Nursing. 3rd ed. Hudson, Ohio: Lexi-Comp Inc; 2001.

By Ellen M. Prewitt, RN, MSN, ACNP, CCRN

Ellen M. Prewitt, RN, MSN, ACNP, CCRN, has been an acute care nurse practitioner since 1995. She currently is an ACNP with Summit County Intensive Care Physicians Inc at Summa Health System, Akron, Ohio.

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