Harrison’s Manual of Medicine



Fever and Hyperthermia
Fever of Unknown Origin (FUO)

Fever and Hyperthermia
Fever is an abnormal elevation of body temperature due to a change in the hypothalamic thermoregulatory center. Although “normal” temperature is said to be 37°C, the maximal normal temperature ranges from 37.2°C (98.9°F) at 6 A.M. to 37.7°C (99.9°F) at 4 P.M. Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings. Fever is caused by a resetting of the hypothalamic “set point” by prostaglandins (especially PGE2), a process mediated by cytokines. Fever may result from infection, immune phenomena, vascular inflammation or thrombosis, infarction or trauma, granulomatous diseases (e.g., sarcoid), inflammatory bowel disease, neoplasms (especially Hodgkin’s disease, lymphoma, leukemia, renal cell carcinoma, and hepatoma), or acute metabolic disorders (e.g., thyroid crisis, Addisonian crisis).
Hyperthermia is an uncontrolled increase in body temperature that exceeds the body’s ability to lose heat without an elevation of the hypothalamic set point. Hyperthermia without fever may result from failure to dissipate body heat adequately (e.g., in a hot environment) or from drugs (e.g., neuroleptic malignant syndrome caused by phenothiazines and other neuroleptics, malignant hyperthermia caused by inhalation anesthetics or succinylcholine in genetically susceptible individuals).
CLINICAL MANIFESTATIONS   In addition to an elevated body temperature, patients with fever may develop generalized symptoms such as myalgias, arthralgias, anorexia, and somnolence. Chills—a sensation of cold— occur with most fevers. Rigors—profound chills—are associated with piloerection, chattering of the teeth, and severe shivering. Sweats accompany the activation of heat-loss mechanisms. Alterations in mental status, including delirium and convulsions, are most common among the very young, the very old, and the debilitated. Rash may occur with fever and may indicate a localized skin eruption or a systemic disease. The distinctive appearance of an eruption in association with a clinical syndrome may facilitate prompt diagnosis and treatment.
DIAGNOSIS   Few signs and symptoms in medicine suggest as many diagnostic possibilities as fever; thus a careful clinical evaluation is necessary. A detailed history must be obtained, including present illness and medical, social, travel, and family history. A meticulous physical exam must be performed and repeated on a regular basis. When rash accompanies fever, special attention should be given to the onset, configuration, arrangement, and distribution of the lesions. (For a more detailed description of systemic illnesses with fever and rash, see Table 18-1 in HPIM-15.) The lab workup must be individualized in light of the clinical circumstances. It should always include a CBC with differential and examination of any abnormal fluid collection (joint, pleural fluid). Other tests to consider include ESR determination, UA, LFTs, and cultures of blood, urine, sputum, or stool. Radiologic tests may include plain radiography, MRI and CT scanning (for detection of abscesses), and radionuclide scanning (esp. tagged WBC scanning). If no diagnosis can be made on the basis of less invasive tests, tissue must be obtained for biopsy, particularly from any abnormal organ; bone marrow biopsy may be useful, esp. for pts with anemia.
Fever of Unknown Origin (FUO)
Classic FUO is diagnosed when fever of >38.3°C (101°F) develops on several occasions over the course of >3 weeks and when 1 week of study in the hospital or three outpatient visits fail to result in a diagnosis. Most cases of FUO are due to infection, neoplasm, or collagen-vascular disease. Other causes include drugs, granulomatous diseases, inflammatory bowel disease, pulmonary embolism, factitious fever, erythema multiforme, familial Mediterranean fever, Behçet’s syndrome, and Fabry’s disease. FUO prolonged beyond 6 months is much less commonly due to infection and more often due to unusual or undetermined causes. When no cause can be identified, the prognosis is usually favorable. Treatment for classic FUO consists of continued observation and examination with avoidance of empirical therapy. Other specialized categories of FUO have been established for certain populations of pts (Table 6-1), with variations in diagnosis and treatment.

Table 6-1 Categories of FUOa

The first decision to make is whether an elevation in body temperature reflects fever or hyperthermia. The objectives in treating fever are to reduce the elevated hypothalamic set point and to facilitate heat loss. There is no evidence that fever itself facilitates recovery from infection. Low-grade or mild fevers do not necessarily require treatment except in pregnant women, children with febrile seizures, or pts with impaired cardiac, pulmonary, or cerebral function. High fever (>41°C) should be managed with antipyretics and with physical cooling with a cooling blanket or sponge bath. Acetaminophen (0.65 g) given every 3 h around the clock (rather than intermittently, which aggravates symptoms of sweats and chills) is effective for the management of most fever and is preferred because it does not (1) mask signs of inflammation that might indicate a cause of the fever, (2) impair platelet function, or (3) cause Reye’s syndrome in children. NSAIDs and aspirin have anti-inflammatory as well as antipyretic effects. NSAIDs may be particularly useful in the management of fever due to malignancy.
By definition, hyperthermia does not respond to attempts to reset the already-normal hypothalamic set point (e.g., with acetaminophen) but does respond to physical cooling with measures such as sponging, fans, cooling blankets, and even ice baths. These measures should be instituted immediately in hyperthermia, and IV fluids should be administered. If insufficient cooling is achieved with these methods, gastric or peritoneal lavage with iced saline can be initiated; in extreme circumstances, hemodialysis or cardiopulmonary bypass with cooling of the blood can be undertaken. Malignant hyperthermia, neuroleptic malignant syndrome, drug-induced hyperthermia, and perhaps hyperthermia due to thyrotoxicosis respond to dantrolene (1–2.5 mg/kg IV q6h). Procainamide should be administered to pts with malignant hyperthermia because of the high risk of ventricular fibrillation in this syndrome.


For a more detailed discussion, see Dinarello CA, Gelfand JA: Fever and Hyperthermia, Chap. 17, p. 91; Kaye ET, Kaye KM: Fever and Rash, Chap. 18, p. 95; and Gelfand JA: Fever of Unknown Origin, Chap. 125, p. 804, in HPIM-15.



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