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Neuroleptic Malignant Syndrome
Other Conditions

For centuries, fever has been recognized as a cardinal sign of disease, and recent scientific studies have provided substantial insight into the mechanisms contributing to a rise in body temperature. The effectiveness of the systems involved in thermoregulation explains why body temperatures in excess of 41°C (106°F) are unusual in adults. By considering the limited number of conditions associated with extreme elevations of body temperature, reviewing the epidemiologic history, and focusing on the physical examination, the clinician can usually establish a correct diagnosis. Further, because useful therapies exist for all the disorders associated with hyperpyrexia and hyperthermia, a prompt diagnosis can be expected to result in a greater likelihood that the patient will survive the event. Central to the approach to any patient with a temperature above 41°C is a recognition that both the underlying condition and the exaggerated temperature can produce substantial morbidity or death.
In the healthy adult, body temperature is maintained within a narrow range (37°C ± 1°C) by mechanisms that balance the rates of heat production and dissipation and that compensate for environmental changes predisposing to heat gain or loss. “Thermosensors” in the anterior hypothalamus play a pivotal role in maintaining homeostasis by receiving information via the brainstem from the skin and viscera and effecting adjustments through the posterior hypothalamus “set point.” Input from the posterior hypothalamus through the brainstem results in changes in the activity of the endocrine, musculoskeletal, and autonomic nervous systems; these alterations, in turn, produce adjustments in body temperature. A number of neurotransmitters and modulators within the central nervous system (CNS), including dopamine, serotonin, pros-ztaglandins, acetylcholine, and neuropeptides, contribute to temperature regulation. Basal heat production, which is modulated by thyroid hormones and catecholamines, is a product of essential metabolic processes. The rate of heat production can be increased up to 10-fold by shivering or intense physical exercise. Changes in dermal blood flow, which is regulated through cholinergic nerve activity, permit heat conservation (vasoconstriction) or facilitate heat dispersion (vasodilation). Finally, heat can be transferred from the skin to the atmosphere by a number of mechanisms, especially evaporation (sweating).
Induced by infectious disease, fever (or pyrexia) represents a disorder of thermoregulation in which the hypothalamic set point of the host rises, resulting in a rise in temperature produced by peripheral vasoconstriction and shivering. The elevated body temperature appears to enhance host defenses against a variety of viral, bacterial, and mycobacterial pathogens. Rarely exceeding 41°C, the temperature elevation associated with infection is mediated by the products of monocytes and other cells (“endogenous pyrogens”), including interleukin-1, interleukin-6, and tumor necrosis factor. These cytokines induce the synthesis of prostaglandin E2 by endothelial cells within the CNS, resulting in the “resetting” of the hypothalamus and a rise in body temperature. The generation of interleukin-1 and the other endogenous pyrogens is usually triggered by “exogenous pyrogens”; these include components of bacterial cell walls, such as lipopolysaccharide (endotoxin) from gram-negative bacilli, and toxins, such as the staphylococcal toxic shock toxin and the streptococcal pyrogenic exotoxins.
In contrast to an increased body temperature resulting from infection, hyperthermia represents a condition in which regulatory mechanisms fail to compensate for heat gain; in this circumstance, the hypothalamic set point remains unchanged. Temperatures in excess of 42.2°C (108°F) are not uncommon in hyperthermal states, and they tend to be self-perpetuating. More important, because enzyme denaturation, protein coagulation, and lipid liquefaction in the brain and other vital organs tend to commence at about 42°C (107.6°F), sustained hyperthermia is ultimately injurious to the patient. Patients may experience a rise in body temperature that is precipitated by an infectious illness but exaggerated by inadequacies in heat-dissipating mechanisms; for example, temperatures higher than 41°C are occasionally observed in quadriplegic patients with autonomic nervous system dysfunction and common infections, such as pyelonephritis. Thus, a distinction between hyperpyrexia and hyperthermia may be difficult to appreciate in some cases. Of note, hyperthermia enhances the tumoricidal activity of ionizing radiation, chemotheraputic drugs, and perhaps radioimmunotherapy agents; indeed, the use of local hyperthermia (i.e., intravesicular and intraperitonal) in combination with radiotherapy and chemotherapy to treat malignancies is under active investigation.
Fortunately, infectious diseases are not commonly associated with hyperpyrexia. For example, in studies of large numbers of adults who were treated during the pre-antimicrobial era for lobar pneumonia and other serious infections, temperatures of 41°C or higher were noted in fewer than 5% of recordings. Because the clinical characteristics of patients with extreme pyrexia were not detailed in these older reports, the factors beyond infection that may have contributed to the high temperatures are not known. In more contemporary surveys of febrile patients, extreme pyrexia has been observed in patients with pneumonia, gram-negative bacteremia, staphylococcal bacteremia, pyelonephritis, and malaria. In many cases, the hyperpyrexia is associated with both infection and impaired thermoregulation caused by heatstroke, extensive burns, paraplegia, quadriplegia, and other diseases of the CNS. Extreme pyrexia does not appear to produce an increased risk for immediate death; however, many patients who survive the febrile episode subsequently succumb to underlying diseases. Among infants and young children, temperatures higher than 41°C have been observed in fewer than 1% of patients presenting to emergency departments for evaluation. Between 12% and 50% of children with hyperpyrexia will have serious bacterial infections, including pneumonia, bacteremia, and meningitis; these infections are usually caused by Streptococcus pneumoniae, Haemophilus influenzae, group B streptococci, or Escherichia coli.
In summary, although uncommon, hyperpyrexia can be a manifestation of infection in adults (and children). Consequently, if the etiology of a substantial temperature elevation is unclear at presentation, blood cultures and other routine tests to detect bacterial infection should be obtained promptly, and empiric antimicrobial therapy should be initiated. In the adult, the initial therapy should cover gram-negative bacilli (E. coli, Klebsiella pneumoniae) and Staphylococcus aureus; accordingly, a fluoroquinolone, a third-generation cephalosporin, aztreonam, or an aminoglycoside plus oxacillin or vancomycin would be appropriate. The selection of specific agents will be guided by a variety of factors, including the setting in which the pyrexia evolved (community-acquired vs. nosocomial illness), nature of underlying diseases, results of Gram’s stains of clinical specimens, drug allergy history, and presence of abnormal or changing renal function.
Neuroleptic Malignant Syndrome
The neuroleptic malignant syndrome represents a condition that can be confused with sepsis. An idiosyncratic reaction first described in the 1960s, the disorder remains an occasionally unrecognized and potentially lethal complication of neuroleptic drug therapy. Several observations indicate that a reduction in dopaminergic activity within the CNS plays a central role in precipitating the syndrome. First, the drugs associated with the disorder are known to be antidopaminergic, and the potential for a drug to induce the illness appears to parallel its activity as a dopamine antagonist. Second, the symptoms of the disorder can be explained by dopamine receptor blockade within the hypothalamus and basal ganglia. Finally, the manifestations of the syndrome can be treated with bromocriptine, a potent dopamine agonist. The hyperthermia appears to result from changes in the hypothalamic set point and an increase in heat production caused by a generalized contraction of muscles.
The factors that precipitate the neuroleptic malignant syndrome in susceptible persons remain poorly defined. Nevertheless, underlying conditions, such as organic brain disease, dehydration, and exhaustion, seem to predispose patients to the disorder; on occasion, an intercurrent infectious illness, such as a urinary tract infection, appears to trigger the hyperthermal episode. The importance of these precipitating factors is illustrated by the fact that most patients who experience the syndrome will not have a recurrence when rechallenged with neuroleptics.
The neuroleptic malignant syndrome usually occurs in association with the use of a dopamine-blocking agent, including a butyrophenone (haloperidol), thioxanthene (thiothixene), or phenothiazine (fluphenazine, chlorpromazine, thioridazine, perphe-nazine, trimeprazine, prochlorperazine); haloperidol, alone or in combination with other medications, represents the most frequently identified offending drug. Finally, the syndrome can also evolve following the withdrawal of dopamine agonists (amantadine, levodopa, carbidopa) and during treatment with dopamine-depleting drugs (tetrabenazine, a-methyltyrosine). The syndrome can appear soon after initiation of neuroleptic therapy or following dosage adjustments in patients on long-term treatment. The disorder typically occurs in patients given therapeutic doses of the drugs. Although usually seen in patients with serious psychiatric disease (schizophrenia, manic-depressive illness), the syndrome has also been reported in normal patients given neuroleptic agents as part of preinduction anesthesia or for the management of sedative-hypnotic withdrawal.
Abrupt in onset and rapidly progressing during 24 to 72 hours, the neuroleptic malignant syndrome usually begins with the appearance of involuntary movements and generalized “lead pipe” or “plastic” muscular rigidity. Dystonic movements, tremors, and facial grimacing are prominent signs. Dysarthria, dysphagia, and sialorrhea result from hypertonicity of the pharyngeal muscles. Catatonic behavior can be present. The level of consciousness fluctuates and ranges from an alert mutism to stupor or coma. Signs of autonomic dysfunction include pallor, tachycardia, labile blood pressure, profuse diaphoresis, and urinary incontinence. Hyperthermia characteristically follows the occurrence of extrapyramidal rigidity. The laboratory abnormalities are nonspecific but commonly include a leukocytosis and an elevated serum creatine phosphokinase, the latter resulting from myonecrosis induced by intense and sustained muscle contractions. Myoglobinuria can lead to acute renal failure.
Lethal catatonia should be included in the differential diagnosis of the psychiatric patient with an abnormal mental status and hyperthermia. Patients with lethal catatonia typically have a history of intense excitement, anxiety, or physical activity lasting for weeks; the initial symptoms are hallucinations, delusions, and self-destructive or assaultive behavior. The activity of the patient with lethal catatonia precludes adequate nutrition and hydration, and it leads to exhaustion. Thus, in lethal catatonia, psychosis precedes the onset of the catatonic state. In contrast to lethal catatonia, the neuroleptic malignant syndrome develops over hours to days, and the condition is not associated with severe excitement or anxiety. Because the therapy of lethal catatonia may include neuroleptic agents, the importance of excluding a diagnosis of neuroleptic malignant syndrome is apparent.
Malignant hyperthermia represents a second condition that can present with manifestations similar to those of the neuroleptic malignant syndrome. A disorder of skeletal muscle, malignant hyperthermia occurs in genetically susceptible persons. The illness is characterized by generalized muscular contractions, which produce rigidity, hyperthermia, rhabdomyolysis, hyperkalemia, and shock. Malignant hyperthermia is precipitated by exposure to halogenated inhalational anesthetics or depolarizing agents such as succinylcholine; these substances induce changes in skeletal muscle membranes, resulting in an excessive calcium influx and sustained contraction. Therapy for malignant hyperthermia is directed at relaxing the contracting muscles, and dantrolene sodium is the drug of choice.
Although the definitive therapy for the neuroleptic malignant syndrome has not been established, a number of interventions appear useful in treating the condition. The offending drugs should be withdrawn, and supportive measures should be initiated, including hydration and external cooling. Dantrolene sodium, a peripheral muscle relaxant, reduces the spasticity and related symptoms. Dantrolene can be administered by mouth or nasogastric tube at a dose of 50 to 200 mg/d or intravenously at a dose of 0.8 to 10 mg/kg daily; the initial IV dose should be 2 to 3 mg/kg daily. Bromocriptine, a dopamine agonist, usually produces a rapid resolution of all clinical manifestations of the illness; bromocriptine can be given orally or by nasogastric tube at a dose of 2.5 to 10 mg three to four times daily. On occasion, therapy with both dantrolene sodium and bromocriptine has been used with success. However, even with drug therapy, complete resolution of the problem can require 9 to 10 days. Patients who received a depot neuroleptic (fluphenazine) are at risk to experience a relapse of the syndrome; thus, they may require prolonged therapy. Pneumonia, pulmonary emboli, and soft-tissue infections can complicate the neuroleptic malignant syndrome, and these intercurrent problems should be suspected when fever persists or recurs in patients apparently cured of the disorder.
The mortality rate for patients with the neuroleptic malignant syndrome is 5% to 20%; recent case-control studies have indicated that dantrolene and bromocriptine have reduced fatality rates by approximately 50%. Because of an increased awareness of the problem and a reduced use of IM neuroleptics, the incidence of the syndrome appears to be declining. In the majority of cases, the neurologic recovery is complete; on occasion, cognitive defects secondary to CNS damage persist.
The most common cause of hyperthermia in adults is heatstroke, a life-threatening condition that is precipitated by environmental factors and results from a failure of heat-dissipating mechanisms, especially sweating. At ambient temperatures above 35°C (95°F), heat loss becomes dependent on the evaporation of sweat. The rate of evaporation is influenced by the relative humidity and air movement; thus, as the humidity rises and air flow decreases, sweating becomes less efficient, and the body temperature tends to increase. Heat cramps and heat exhaustion are milder clinical syndromes produced by excessive environmental heat. Heatstroke typically occurs when someone is suddenly exposed to unusually hot and humid conditions for more than 48 hours. Epidemic heatstroke is observed in cities that experience cold winters followed by hot weather and high humidity during the late spring or early summer. Among the conditions that enhance susceptibility to heatstroke are advanced age, alcoholism, heart disease, obesity, incidental infection, and certain medications, especially anticholinergics and major tranquilizers (phenothiazines, butyrophenones). Military personnel, laborers, athletes, and other young adults who exercise strenuously in hot, moist environments are at risk for the development of exertional heatstroke; risk factors for this condition include heavy clothing or protective equipment, drugs that impair heat loss (including illegal agents, such as cocaine and amphetamines), obesity, poor physical condition, and volume depletion.
Most patients with heatstroke experience prodromal symptoms, such as headache, dizziness, weakness, nausea, and a feeling of warmth, for 2 to 4 days before seeking medical attention. Up to 75% of patients notice decreased sweating shortly before hospitalization. The primary manifestations of heatstroke are hyperthermia, hot and dry skin, and CNS disturbances, including delirium, stupor, and coma. Hypotension, electrolyte disturbances, renal dysfunction, and coagulation abnormalities are common findings. Rhabdomyolysis and lactic acidosis can be prominent in patients with exertional heatstroke; acute hepatic necrosis can also occur. Infection is an uncommon precipitant of heatstroke; however, pneumonia has been found at presentation in some elderly heatstroke victims, and gram-negative bacilli (E. coli, Klebsiella, Pseudomonas) and S. aureus have been isolated from these patients. On rare occasion, meningitis will also be present.
The cornerstone of therapy for heatstroke remains external, whole-body cooling. Patients should be immersed in cold water or packed in ice and massaged. These aggressive cooling measures can usually be discontinued when the core body temperature falls below 39.4°C (103°F). Ice water lavage or enemas are not recommended. Phenothiazines should not be used to control shivering, and dantrolene sodium plays no role in the management of patients with this condition. Because pooling of blood in cutaneous vessels may contribute to hypotension, fluid should be administered judiciously during the period of external cooling; if the blood pressure does not rise as the body temperature falls and following the infusion of normal saline, a Swan-Ganz catheter should be inserted to permit a more accurate assessment of fluid requirements. Complications of heatstroke, including seizures, cardiac arrhythmias, metabolic acidosis, hyperkalemia, and renal failure, also require prompt identification and therapy. Aged patients with heatstroke must be carefully evaluated for concomitant pyogenic infection, especially pneumonia. Patients who survive heatstroke can have residual neurologic sequelae; these include focal defects, such as cerebellar dysfunction or hemiplegia, and a decline in intellectual capacity, ranging from a mild confusional state to a frank dementia.
Other Conditions
Resembling exertional heatstroke in etiology, cocaine-associated hyperthermia appears to be triggered by a myriad of drug-related phenomena, including exaggerated physical exercise, increased sympathetic activity, impaired heat loss, and seizures. Obtundedness, rhabdomyolysis, renal failure, coagulopathy, acidosis, and hepatic injury are characteristic. External cooling represents the cornerstone of therapy. Amphetamines, phenylpropanolamine, mescaline, and phencyclidine are other illicit drugs that are associated with hyperthermia. On occasion, salicylate overdose can produce temperatures in excess of 41°C; serum salicylate levels in these cases are typically greater than 1,000 g/mL.
A few other conditions are associated with substantial temperature elevations. Temperatures above 41°C may be the primary manifestation of factitious disease. A factitious illness should be suspected in a young female patient who is a student, nurse, or medical technologist and who has an enigmatic illness that is characterized by extreme temperature elevations without concomitant tachycardia, warm skin, diaphoresis, or signs of serious systemic illness. To achieve the dramatic temperature elevations that guarantee medical attention, patients with factitious fever often heat the thermometer by exposing it to a lamp or immersing it in hot water. Finally, tetanus, the toxic shock syndrome, CNS diseases (tumors, encephalitis, hemorrhage), and endocrine disorders (thyroid storm, pheochromocytoma) will occasionally produce temperatures exceeding 41°C. (A.L.E.)
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Surgical anesthesia can trigger a pheochromocytoma-related crises.
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Hyperthyroidism and hyperthermia can be precipitated by anesthesia.
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In this retrospective review of 108 children with temperatures greater than 41°C evaluated in an emergency department, 12% had serious bacterial infections, including 3% with meningitis.
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A detailed and extensively referenced discussion of these distinct but potentially confused conditions.
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The authors provide a review of malignant hyperthermia, neuroleptic malignant syndrome, sympathomimetic poisoning, and anticholinergic toxicity.
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A contemporary review of the problem and its management.
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A contemporary review of the mechanisms involved in the generation of fever, with emphasis on cytokines and the acute-phase response.
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In an analysis of 357 patients with serious infectious diseases, only 4.3% of 1,761 temperature recordings were 41°C or higher.
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The failure of electronic thermometers or monitoring devices can produce very high temperature recordings.
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Treated with a standard protocol that included the use of ice, a tepid water spray, massage, and a fan, the patients experienced rapid cooling, a low mortality rate, and complete neurologic recovery.
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The authors describe a middle-aged patient whose core body temperature rose above 43°C following an amitryptyline overdose.
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The author provides a useful approach to the patient suspected of having these conditions.
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Growth hormone deficiency is associated with reduced sweating, a condition that can lead to hyperthermia.
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The investigators document a significant fall in the incidence of the disorder at one psychiatric center; they attribute the decline in attack rate to a reduction in the use of IM neuroleptics.
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The amphetamine derivatives, ecstasy and eve, can cause hyperthermia, liver necrosis, cerebral and cardiac injury, and death.
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In this study with six healthy volunteers, the authors compared heat transfer and cooling rates with five techniques (circulating water mattress, forced cold air, gastric lavage, bladder lavage, and immersion in ice water); immersion in ice water slurry produced the most rapid rate of heat loss and the largest decrease in core body temperature.
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Of 20 patients who experienced the disorder, 11 resumed neuroleptic therapy and had no recurrence, which indicates that factors beyond the drugs contributed to evolution of the syndrome.
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The authors describe 12 patients with hyperthermia resulting from intoxication with stimulants, anticholinergics, salicylates, or combinations of these drugs; five died, and four had severe neurologic sequelae.
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This detailed analysis of the published data concerning the efficacy of dantrolene and bromocriptine concludes that the addition of either agent to supportive management shortens the time to clinical response from 6.8 days to approximately 1 day.
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In this retrospective analysis, the mortality rate for the controls was found to be 21%; for patients treated with dantrolene or bromocriptine, the rates were 8.6% and 7.8%, respectively.
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Of 28 patients with hyperpyrexia seen at the Massachusetts General Hospital between 1970 and 1975, 71% had an infectious illness, usually caused by a gram-negative bacillus.
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An overview of the physiology of temperature regulation and a discussion of selected conditions associated with hyperthermia.
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The authors review long-lasting cognitive impairments experienced by some patients with neuroleptic malignant syndrome.
Walter FG, et al. Marijuana and hyperthermia. J Toxicol Clin Toxicol 1996;34:217.
The authors report the first case of hyperthermia associated with marijuana use and jogging.

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