Chapter 017. Fever and Hyperthermia (Part 6) 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. 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 patients is highly 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 CNS 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. Attempts to lower the already normal hypothalamic set point are of little use. Physical cooling with sponging, fans, cooling blankets, and even ice baths should be initiated immediately in conjunction with the administration of IV 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 IV administration of dantrolene sodium. The recommended dose of dantrolene is 1– 2.5 mg/kg given intravenously every 6 h for at least 24–48 h—until 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 the serotonin syndrome and 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. Acknowledgment The substantial contributions of Jeffrey A. Gelfand to this chapter in previous editions are gratefully acknowledged. FURTHER READINGS De Koning HD et al: Beneficial response to anakinra and thalidomide in Schnitzler's syndrome. Ann Rheum Dis 65:542, 2006 Dinarello CA: Infection, fever, and exogenous and endogenous pyrogens: Some concepts have changed. J Endotoxin Res 10:202, 2004 Hawkins PN et al: Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 50:607, 2004 [PMID: 14872505] Hoffman HM et al: Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 364:1779, 2004 [PMID: 15541451] Keane J et al: Tuberculosis associated with infliximab, a tumor necrosis factor-α-neutralizing agent. N Engl J Med 345:1098, 2001 [PMID: 11596589] Pascual V et al: Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med 201:1479, 2005 [PMID: 15851489] Simon A, van der Meer JW: Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. Am J Physiol Regul Integr Comp Physiol 292:R86, 2007 ——— et al: Beneficial response to interleukin-1 receptor antagonist in TRAPS. Am J Med 117:208, 2004 Wallis RS et al: Differential effects of TNF blockers on TB immunity. Ann Rheum Dis 64(Suppl3):132, 2005 ——— et al: Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 38:1261, 2004 BIBLIOGRAPHY Atkins E: Pathogenesis of fever. Physiol Rev 40:580, 1960 [PMID: 13794961] Bouchama A, Knochel JP: Heat stroke. N Engl J Med 346:1978, 2002 [PMID: 12075060] Chandrasekharan NV et al: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proc Natl Acad Sci USA 99:13926, 2002 [PMID: 12242329] Dinarello CA: Differences between anti-tumor necrosis factor-alpha monoclonal antibodies and soluble TNF receptors in host defense impairment. J Rheumatol Suppl 74:40, 2005 [PMID: 15742464] ———: Proinflammatory cytokines. Chest 118:503, 2000 Fitzgerald AA et al: Rapid responses to anakinra in patients with refractory adult-onset Still's disease. Arthritis Rheum 52:1794, 2005 [PMID: 15934079] Goldbach-Mansky R et al: Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 355:581, 2006 [PMID: 16899778] Mackowiak PA: Physiological rationale for suppression of fever. Clin Infect Dis 31:S185, 2000 ———: Concepts of fever. Arch Intern Med 158:1870, 1998 ———: Fever: Basic Mechanisms and Management, 2d ed. Philadelphia, Lippincott-Raven, 1997 ———: Carl Reinhold August Wunderlich and the evolution of clinical thermometry. Clin Infect Dis 18:458, 1994 ———, Wasserman SS: A critical appraisal of 98.6˚F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA 268:1578, 1992 Netea MG et al: Circulating cytokines as mediators of fever. Clin Infect Dis 31:178, 2000 Ushikubi F et al: Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 395:281, 1998 [PMID: 9751056] Wolff SM: Biological effects of bacterial endotoxins in man. J Infect Dis 128:733, 1973 Yang RB et al: Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signaling. Nature 395:284, 1998 [PMID: 9751057] . Chapter 017. Fever and Hyperthermia (Part 6) Regimens for the Treatment of Fever The objectives in treating fever are first to reduce the elevated hypothalamic set point and second. 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. preparations of NSAIDs and rectal suppository preparations of various antipyretics can be used.Treatment of fever in some patients is highly recommended. Fever increases the demand for oxygen (i.e.,