FEVER AND HYPERTHERMIA 3

TREATMENT

The Decision to Treat Fever Most fevers are associated with self-limited infections, most commonly of viral origin. In these cases, the general cause of the fever is easily identified. The routine use of antipyretics given automatically as "standing," "routine," or "prn" orders to treat low-grade fevers in adult patients on hospital wards is entirely unacceptable. This practice masks not only fever but also other important clinical indicators of a patient's course. The assumption underlying any decision to reduce fever with antipyretics is that there is no diagnostic benefit to be gained by allowing the fever to persist. However, there may be such a diagnostic benefit. For example, the daily highs and lows of normal temperature are exaggerated in most fevers, but the usual times of peak and trough temperatures may be reversed in typhoid fever and disseminated tuberculosis. Temperature-pulse dissociation (relative bradycardia) occurs in typhoid fever, brucellosis, leptospirosis, some drug-induced fevers, and factitious fever. In newborns, the elderly, patients with chronic renal failure, and patients taking glucocorticoids, fever may not be present despite infection, or core temperature may be hypothermic. Hypothermia is observed in patients with septic shock.

Some febrile diseases have characteristic patterns. With relapsing fevers, febrile episodes are separated by intervals of normal temperature; when paroxysms occur on the first and third days, the fever is called tertian. Plasmodium vivax causes tertian fevers. Quartan fevers are associated with paroxysms on the first and fourth days and are seen with P. malariae. Other relapsing fevers are related to Borrelia infections and rat-bite fever, which are both associated with days of fever followed by a several-day afebrile period and then a relapse of days of fever. Pel-Ebstein fever, with fevers lasting 3 to 10 days followed by afebrile periods of 3 to 10 days, is classic for Hodgkin's disease and other lymphomas. Another characteristic fever is that of cyclic neutropenia, in which fevers occur every 21 days and accompany the neutropenia. There is no periodicity of fever in patients with familial Mediterranean fever.

Mechanisms of Antipyretic Agents The synthesis of PGE2 depends on the constitutively expressed enzyme cyclooxygenase. The substrate for cyclooxygenase is arachidonic acid released from the cell membrane, and this release is the rate-limiting step in the synthesis of PGE2. Inhibitors of cyclooxygenase are potent antipyretics. The antipyretic potency of various drugs is directly correlated with the inhibition of brain cyclooxygenase. Acetaminophen is a poor cyclooxygenase inhibitor in peripheral tissue and is without noteworthy anti-inflammatory activity; in the brain, however, acetaminophen is oxidized by the p450 cytochrome system, and the oxidized form inhibits cyclooxygenase activity.

Oral aspirin and acetaminophen are equally effective in reducing fever in humans. Nonsteroidal anti-inflammatory agents (NSAIDs) such as indomethacin and ibuprofen are also excellent antipyretics. Chronic high-dose therapy with antipyretics such as aspirin or the NSAIDs used in arthritis does not reduce normal core body temperature. Thus, PGE2 appears to play no role in normal thermoregulation.

As effective antipyretics, glucocorticoids act at two levels. First, similar to the cyclooxygenase inhibitors, glucocorticoids reduce PGE2 synthesis by inhibiting the activity of phospholipase A2, which is needed to release arachidonic acid from the cell membrane. Second, glucocorticoids block the transcription of the mRNA for the pyrogenic cytokines.

Drugs that interfere with vasoconstriction (phenothiazines, for example) can act as antipyretics, as can drugs that block muscle contractions. However, these agents are not true antipyretics since they can also reduce core temperature independently of hypothalamic control.

Indications and Regimens for the Treatment of Fever The objectives in treating fever are first to reduce the elevated hypothalamic set point and second to facilitate heat loss. There is no evidence that fever itself facilitates the recovery from infection or acts as an adjuvant to the immune system. In fact, peripheral PGE2 production is a potent immunosuppressant. Hence, treating fever and its symptoms does no harm and does not slow the resolution of common viral and bacterial infections. Reducing fever with antipyretics also reduces systemic symptoms of headache, myalgias, and arthralgias.

Oral aspirin and NSAIDs effectively reduce fever but can adversely affect platelets and the gastrointestinal tract. Therefore, acetaminophen is preferred to all of these agents as an antipyretic. In children, acetaminophen must be used because aspirin increases the risk of Reye's syndrome. If the patient cannot take oral antipyretics, parenteral preparations of NSAIDs and rectal suppository preparations of various antipyretics can be used.

Treatment of fever in some patient groups is recommended. Fever increases the demand for oxygen (i.e., for every increase of 1°C over 37°C, there is a 13% increase in oxygen consumption) and can aggravate preexisting cardiac, cerebrovascular, or pulmonary insufficiency. Elevated temperature can induce mental changes in patients with organic brain disease. Children with a history of febrile or nonfebrile seizure should be aggressively treated to reduce fever, although it is unclear what triggers the febrile seizure and there is no correlation between absolute temperature elevation and onset of a febrile seizure in susceptible children.

In hyperpyrexia, the use of cooling blankets facilitates the reduction of temperature; however, cooling blankets should not be used without oral antipyretics. In hyperpyretic patients with central nervous system disease or trauma, reducing core temperature mitigates the ill effects of high temperature on the brain.

Treating Hyperthermia A high core temperature in a patient with an appropriate history (e.g., environmental heat exposure or treatment with anticholinergic or neuroleptic drugs, tricyclic antidepressants, succinylcholine, or halothane) along with appropriate clinical findings (dry skin, hallucinations, delirium, pupil dilation, muscle rigidity, and/or elevated levels of creatine phosphokinase) suggests hyperthermia. The attempt to lower the already normal hypothalamic set point is of little use. Physical cooling with sponging, fans, cooling blankets, and even ice baths should be initiated immediately in conjunction with the administration of intravenous fluids and appropriate pharmacologic agents (see below). If insufficient cooling is achieved by external means, internal cooling can be achieved by gastric or peritoneal lavage with iced saline. In extreme circumstances, hemodialysis or even cardiopulmonary bypass with cooling of blood may be performed.

Malignant hyperthermia should be treated immediately with cessation of anesthesia and intravenous administration of dantrolene sodium. The recommended dose of dantrolene is 1 to 2.5 mg/kg of body weight given intravenously every 6 h for at least 24 to 48 h¾until oral dantrolene can be administered, if needed. Procainamide should also be administered to patients with malignant hyperthermia because of the likelihood of ventricular fibrillation in this syndrome. Dantrolene at similar doses is indicated in the neuroleptic malignant syndrome and in drug-induced hyperthermia and may even be useful in the hyperthermia of thyrotoxicosis. The neuroleptic malignant syndrome may also be treated with bromocriptine, levodopa, amantadine, or nifedipine or by induction of muscle paralysis with curare and pancuronium. Tricyclic antidepressant overdose may be treated with physostigmine.