Chapter 111. Hyperthermia

• Heat stroke is distinguished from less severe forms of environmental hyperthermia by higher body temperature and the presence of severe central nervous system dysfunction.
• Classic (nonexertional) heat stroke affects the elderly and the chronically ill and is associated with high morbidity and mortality rates.
• Exertional heat stroke affects younger individuals who exercise in hot environments, and it develops over a short period.
• Immediate conductive or evaporative cooling should be instituted for heat stroke victims with a core temperature above 41°C.
• Malignant hyperthermia is a rare syndrome of hyperthermia, muscle contractions, and cardiovascular instability triggered by succinyl choline and inhaled anesthetics.
• Management of malignant hyperthermia includes the prompt recognition of the syndrome, discontinuation of the inciting drug, administration of dantrolene, and supportive care.
• Neuroleptic malignant syndrome is an idiosyncratic reaction to neuroleptic drugs characterized by hyperthermia, muscle rigidity, alterations in mental status, autonomic dysfunction, and rhabdomyolysis.
• Treatment of neuroleptic malignant syndrome includes discontinuation of the triggering drug, administration of dantrolene for muscle rigidity and hyperthermia, administration of dopaminergic drugs such as bromocriptine and amantadine, and supportive care.

Hyperthermia is defined as a core body temperature above 38.2°C (101.8°F) and is commonly present in patients in the intensive care unit. In most cases, hyperthermia is a consequence of the presence of pyrogens that reset the hypothalamic thermoregulatory mechanism to a higher temperature.1 This response, referred to as fever, is part of the individual's immune response to infection, malignancy, inflammation, or autoimmune disease.

The disorders discussed in this chapter, environmental hyperthermia, malignant hyperthermia, and the neuroleptic malignant syndrome, are not part of the body's immune response and result from a failure of homeostatic thermoregulatory mechanisms. Prompt recognition and appropriate treatment of these syndromes are critical to prevent irreversible cellular and organ injury.

Pathophysiology

Environmental hyperthermia is related to endogenous heat production, high ambient temperatures, and/or high humidity. Humans produce approximately 50 to 60 kcal/m2 per hour of heat, or approximately 100 kcal/hour.2 Minimal activity can increase heat production two- to fourfold, and strenuous exercise may increase heat production as much as 20 times the baseline level. Normally, most heat loss (50% to 70%) occurs from the skin and lungs through radiation in neutral environments. Conduction of heat through direct contact with cooler objects or loss of heat due to convection accounts for a smaller percentage of heat loss. Evaporation of sweat from the skin is a major mechanism of heat loss in a warm environment.

The preoptic nucleus of the anterior hypothalamus receives information from temperature-sensitive receptors in the skin, viscera, and great vessels and initiates physiologic responses to temperature increases. Increased temperatures result in cutaneous vasodilation, decreased muscle tone, and increase in sweating. As ambient temperature nears 37°C (98.6°F), the body relies primarily on evaporation of sweat as a cooling mechanism. Evaporation can result in the loss of 580 kcal/L of evaporated sweat. Conditions of high humidity (>75%) impair the loss of heat through evaporation and increase the risk of heat injury.

An acute phase inflammatory response may cause or contribute to the pathophysiology of heat stroke. Increased concentrations of endotoxin, tumor necrosis factor, soluble tumor necrosis factor receptor, and interleukin 1 have been demonstrated in patients with classic heat stroke (CHS).3,4 Interleukin 6 and nitric oxide metabolite concentrations correlate with the severity of illness. Endothelial cell activation or injury is suggested by findings of increased concentrations of circulating intracellular adhesion molecule 1, endothelin, and von Willebrand factor antigen.5 Altered expression or blocked activity of protective heat shock proteins may also contribute to injury in heat stroke.6

Predisposing Factors

Environmental hyperthermia results from increased heat production and/or decreased heat loss (Table 111-1). Environmental heat stress includes high heat and humidity that contribute to heat production and limit heat loss. Numerous drugs interfere with the thermoregulatory process. Sympathomimetic drugs, such as amphetamines, cocaine, phencyclidine, ecstasy and ephedrine, increase muscle activity and heat production and may also disrupt hypothalamic regulatory mechanisms.7 Drugs with anticholinergic effects, such as cyclic antidepressants, antihistamines, and antipsychotics, inhibit cholinergically mediated sweating and disrupt hypothalamic function. Ethanol may contribute to heat stroke by several mechanisms: vasodilation resulting in heat gain from the environment, impaired perception of the environment, and diuresis. β-Adrenergic blockers may impair the cardiovascular compensation of increased output needed to compensate for cutaneous vasodilation and decrease cutaneous blood flow. Patients with stroke or head injury may also have impaired regulatory mechanisms. Dehydration by itself has been documented to increase core body temperature. Obese individuals have a lower ratio of body surface area to mass than do the nonobese, which limits radiant heat loss. Loss of apocrine sweat glands due to skin conditions such as burns or scleroderma is a much less common risk factor for heat injury. Factors that increased the risk of death in the July 1995 heat wave in Chicago included being confined to bed due to medical problems and living alone.8

Spectrum of Heat Injury

The most commonly described types of heat injury include heat cramps, heat exhaustion, and heat stroke. Heat cramps are unlikely to result in the need for critical care. Heat cramps usually occur in individuals who work or exercise for long periods in hot environments, sweat heavily, and consume large quantities of hypotonic fluid.9 Heat cramps often occur after exertion in abdominal, thigh, and calf muscles. The etiology is thought to be due to shifts of electrolytes and water between intracellular and extracellular spaces. Many patients experiencing heat cramps never present for medical care. Management includes rest and hydration (intravenously or orally) with a salt solution.

Heat exhaustion also does not usually require intensive care, but it is an important syndrome to distinguish from heat stroke. It may complicate other critical illness such as myocardial infarction and stroke. Patients with heat exhaustion usually experience salt or water depletion as a result of heat stress. Temperatures can be mildly elevated (<40°C), but other clinical manifestations are nonspecific. Patients may complain of malaise, weakness, irritability, nausea, vomiting, and heat cramps. Although patients may have headache and/or mild confusion, severe disturbances of central nervous system (CNS) function are not present. Tachycardia and orthostatic hypotension may suggest significant dehydration. Treatment includes rest in a cool environment and fluid replacement based on clinical and laboratory parameters.

Heat stroke is the syndrome most likely to require intensive care, and it results from failure of normal homeostatic thermoregulatory mechanisms. The diagnosis of heat stroke requires a history of exposure to a heat load (external or internal), severe CNS dysfunction, and elevated temperature (usually gt; 40°C, or >104°F). The absolute temperature may not be critical because cooling measures are often instituted before the patient is admitted to a health care facility. An alternative definition for heat stroke has been proposed that takes into account the current understanding of the pathophysiology: “A form of hyperthermia associated with a systemic inflammatory response leading to a syndrome of multiorgan dysfunction in which encephalopathy predominates.”6 The presence of severe CNS abnormalities distinguishes heat stroke from less severe forms of heat injury such as heat exhaustion. The absence of sweating is not a useful diagnostic criterion. If the history is inadequate, other disorders associated with hyperthermia must be considered in the differential diagnosis, such as infection, hypothalamic injury, thyrotoxicosis, neuroleptic malignant syndrome, and malignant hyperthermia.

Heat Stroke Syndromes

Two syndromes of heat stroke occur: classic (nonexertional) heat stroke (CHS) and exertional heat stroke (EHS). CHS typically affects elderly individuals with underlying chronic illness and tends to occur when environmental heat stress is maximal for several days. This syndrome usually develops over several days and results in significant dehydration and absence of sweating.

EHS typically occurs in young, healthy individuals such as amateur athletes and military recruits who exercise in hot environments. This syndrome occurs sporadically depending on initiation of significant activity in a hot environment. These individuals usually have no chronic illness and are more likely to be nonacclimated individuals. Exertional heat stroke can occur over a short period. Dehydration may be mild, and approximately 50% of individuals will have profuse sweating on presentation.

Clinical Manifestations

Heat stroke is a multisystemic disorder, and the manifestations in an individual depend on rapidity of onset, severity of exposure (temperature and duration), and comorbid conditions.10 CNS dysfunction may range from bizarre behavior, delirium, and confusion to decerebrate rigidity, cerebellar dysfunction, seizures, and coma. Cerebellar abnormalities are often the first to appear and the last to resolve. These changes are potentially reversible, although permanent deficits such as cerebellar dysfunction, hemiparesis or dementia can occur. Lumbar puncture in patients with heat stroke may reveal increased protein, xanthochromia, and lymphocytic pleocytosis.

Tachycardia is an almost universal cardiovascular finding in heat stroke unless the patient is receiving β-adrenergic blockers or calcium channel blockers. Tachycardia occurs in response to peripheral vasodilation and the need for increased cardiac output. Supraventricular tachycardia and atrial fibrillation may also occur. The systemic vascular resistance is usually low unless severe hypovolemia is present.11 Compensatory vasoconstriction occurs in the splanchnic and renal vascular beds. If the patient is unable to increase cardiac output, hypotension develops. Reversible myocardial dysfunction has been described in heat stroke,12 and a variety of electrocardiographic changes have been described, including conduction defects, prolonged QT interval, nonspecific STT changes, and STT changes consistent with myocardial ischemia.13 Additional physical examination findings may include ileus, gastric distension, diarrhea, decreased muscle tone, and tachypnea.

Laboratory Findings

The acid-base status in patients with heat stroke may be difficult to predict. Tachypnea may result in significant respiratory alkalosis, but most patients also have a metabolic lactic acidosis.10,14,15 The etiology of the lactic acidosis differs with the type of heat stroke syndrome. In CHS, lactic acidosis more commonly results from hypoperfusion and is often mild. In EHS, lactate is produced as a consequence of anaerobic muscle metabolism and acidosis may be severe. Hypoglycemia may be present in patients with EHS due to increased glucose use and impaired hepatic gluconeogenesis. Rhabdomyolysis with elevation of creatine kinase and renal failure occur more commonly with EHS. Renal failure occurs in approximately 25% of patients with EHS and 5% of patients with CHS. Renal injury may be due to myoglobinuria, direct thermal parenchymal damage, or decreased renal blood flow due to hypotension. Hematologic effects of heat stroke include leukocytosis and hypocoagulability that may progress to disseminated intravascular coagulation (DIC). Coagulation abnormalities may peak hours to days after heat injury.10 Hepatic heat injury results in elevation of bilirubin and transaminase levels. Electrolyte concentrations are variable in heat stroke.14 Hyperkalemia can result from rhabdomyolysis, but hypokalemia occurs more commonly. Hypocalcemia can occur, particularly with rhabdomyolysis, but usually does not require specific therapy.

Treatment of Heat Stroke

In addition to resuscitative measures, immediate cooling should be instituted for any patient with a temperature above 41°C (>105.8°F). Diagnostic testing such as computed tomography should be performed after cooling. Two methods of cooling have been used: conductive cooling and evaporative cooling. Although specific methods are promoted by individual clinicians, definitive human studies are lacking and the optimal cooling method remains controversial. Available resources and personnel may dictate the exact method used. Most patients can be effectively cooled in 30 to 45 minutes with either technique.

Direct cooling by enhancing conduction of heat from the body is accomplished by immersion of the patient in cold water. Skin massage to counter cutaneous vasoconstriction in the limbs has been recommended. Shivering can result in an undesirable increase in heat production, and chlorpromazine has been recommended to prevent this response. However, chlorpromazine may lower the seizure threshold and impair sweating. This method requires considerable staff time and may interfere with other resuscitative measures such as intubation and intravenous access. Variants of this method include ice-water soaks and application of ice packs to the axillae, groin, and neck, where the great vessels are closer to the skin surface. A protocol used by the U.S. Marine Corps training base for EHS has been described as follows16:

• A stretcher holding the victim is placed on top of a bathtub containing water and ice.
• One liter of normal saline is administered intravenously as a bolus.
• Sheets are dipped into the ice water and used to cover and drench the patient.
• Ice is added to the top of the sheet for further cooling and skin is massaged is improve skin blood flow.
• The head is constantly irrigated with more ice water and a fan is directed at the patient.

Evaporative cooling is a widely used cooling method based on a body cooling unit developed in the Middle East for treatment of individuals with heat stroke during the annual pilgrimage to Mecca.17 Optimum cooling was achieved with unclothed volunteers suspended on a net sprayed with 15°C water and warm air at 30°C to 35°C (at the skin surface). A practical adaptation for hospital use is to place the unclothed patient on a stretcher and spray with warm (not cold) water. High-flow air currents are created with the use of fans to enhance evaporative cooling. This method allows personnel to institute other resuscitative measures while cooling occurs.

Other cooling methods such as peritoneal lavage, iced gastric lavage, or cardiopulmonary bypass have not been effectively tested in humans. Dissipation of heat by lavage of body cavities is limited by the small surface area available for conductive heat transfer. Gastric lavage may also predispose to aspiration. Antipyretics are not indicated, and dantrolene is ineffective.18

A thermistor probe (esophageal or rectal) should be used for monitoring core temperature during cooling efforts. Cooling should be stopped at 38.0°C to 38.8°C (100.4°F to 102°F) to prevent hypothermic overshoot. Continued monitoring is needed to detect a subsequent increase in core temperature. In addition to cooling, many patients will require intubation for airway protection. Supplemental oxygen should be instituted for all patients. The type and quantity of intravenous fluids should be individualized based on an assessment of electrolytes, volume status, and urine output. Overaggressive hydration during cooling may result in cardiac decompensation, especially in the elderly as vasodilation corrects. Significant rhabdomyolysis indicates the need to achieve urine outputs of 100 to 200 mL/hour with fluid therapy. Hypotension usually responds to fluid administration and cooling as peripheral vasodilation decreases. Vasopressor agents may result in vasoconstriction and an undesirable decrease in heat exchange. Invasive hemodynamic monitoring may be warranted in patients with refractory hypotension or suspected cardiac impairment. Significant electrolyte abnormalities should be corrected and monitored closely. Benzodiazepines should be used to control any seizure activity. Bleeding secondary to DIC may require transfusion of fresh-frozen plasma and/or platelets.

Outcome from Heat Stroke

The survival rate from heat stroke approaches 90% with appropriate management. However, morbidity rate is related to the duration of hyperthermia and to underlying conditions. Advanced age, severe hypotension, coagulopathy, hyperkalemia, acute renal failure, and prolonged coma are associated with a poor prognosis.14 Elevated lactate levels are associated with a poor prognosis in CHS but not in EHS.19 In a retrospective study, rapid cooling (<1 hour) was associated with decreased mortality rate.20

Malignant hyperthermia (MH) is an inherited drug- or stress-induced hypermetabolic syndrome characterized by hyperthermia, muscle contractures, and cardiovascular instability. The incidence of MH in patients who receive anesthesia with a triggering agent varies in different populations and age groups. The incidence in adults is approximately 1 in 20,000 to 50,000. The syndrome is genetically transmitted as an autosomal dominant trait. Although a similar syndrome in swine is caused by a single-point mutation of the ryanodine receptor, MH in humans is believed to result from a more heterogeneous group of mutations. The syndrome results from defects in calcium transport in skeletal muscle. The primary defects are postulated to be impaired reuptake of calcium into the sarcoplasmic reticulum, enhanced release of calcium from the sarcoplasmic reticulum, and a defect in the calcium-mediated excitation-contraction coupling mechanism. The resultant intracellular hypercalcemia leads to hypermetabolism.

Diagnostic testing for susceptibility to MH is problematic. Currently, a muscle biopsy sample from the patient is exposed in vitro to halothane and caffeine in selected laboratories.21–23 The muscle of an affected individual contracts rather than relaxes in the presence of caffeine or halothane. A normal contracture test does not completely rule out the possibility of MH susceptibility, but no alternate tests are available. This limitation of the test probably reflects the heterogeneous nature of the underlying mutations.

Triggers of Malignant Hyperthermia

Halothane and succinylcholine have been implicated in most reported cases of MH. The combination of the two agents is more commonly involved than either agent alone. Additional potentiating agents include potent inhalational anesthetics, ethanol, caffeine, sympathomimetics (vasopressors), parasympathomimetics (atropine), cardiac glycosides, and quinidine analogues. Less commonly, MH can be precipitated by infection, physical or emotional stress, anoxia or high ambient temperatures. Nondepolarizing neuromuscular blockers, etomidate, nitrous oxide, ketamine, opiates, barbiturates, benzodiazepines, propofol, and local anesthetics are considered safe in patients with MH.

Clinical Manifestations

Manifestations of MH usually occur within 30 minutes of the initiation of anesthesia in 90% of cases. However, the syndrome may occur at any time during anesthesia and the recovery period. The spectrum of presentations ranges from minor symptoms to a fulminant crisis. A clinical grading scale has been devised for diagnosis of MH but is not readily applicable at the bedside, and required data may not be available.24 Muscle rigidity begins in muscles of the extremities or the chest. In patients receiving succinylcholine, the stiffness most commonly begins in the jaw. The development of masseter muscle rigidity after administration of a neuromuscular blocker should be considered an early sign of possible MH.25,26 In the North American MH Registry, masseter muscle rigidity was the first sign in 30% of likely cases.27 However, muscle rigidity may not be present in all cases. Monitoring of arterial blood gases or end-tidal CO2 levels by capnography may detect an increase in CO2 that may be the earliest sign of MH. Tachycardia is an early, although nonspecific, sign. Hypertension and mottling of the skin also occur. The increase in temperature usually occurs later but is followed rapidly by metabolic acidosis, ventricular arrhythmias, and hypotension. Temperature may increase as rapidly as 1°C every 5 minutes. Laboratory abnormalities include increased levels of sodium, calcium, magnesium, potassium, phosphate, creatine kinase, and lactate dehydrogenase and the presence of myoglobinuria. Lactate levels increase, and arterial blood gases indicate hypoxemia and hypercapnia if minute ventilation is constant.

Treatment

Once the diagnosis of MH is considered, the inciting drug should be discontinued immediately and the patient should be ventilated with 100% O2. The most effective and safe therapy is dantrolene, a drug that blocks calcium release from the sarcoplasmic reticulum without inhibiting its reuptake.28 Uncoupling of the excitation-contraction mechanism in skeletal muscle decreases thermogenesis. Dantrolene should be administered by rapid intravenous push at a dose of 2.5 mg/kg and repeated every 5 minutes as needed until the symptoms subside or the maximum dose of 10 mg/kg has been reached. Dantrolene is poorly water soluble and using 40°C water as the diluent may facilitate reconstitution.29 A decrease in muscle rigidity should be evident within minutes. Subsequent doses of 1 mg/kg every 4 to 6 hours should be continued for 36 to 48 hours. If dantrolene is ineffective or slowly effective, evaporative or conductive cooling can also be used. Calcium channel blockers are of no benefit in MH and should not be used to treat arrhythmias. Sodium bicarbonate administration is often recommended to treat the acidosis, but evidence of efficacy is lacking. Urine output, vital signs, and blood gases should be monitored to guide ventilation and fluid therapy. A urine output of 100 to 200 mL/hour may be needed for treatment of rhabdomyolysis and myoglobinuria. Significant hyperkalemia should be treated with intravenous insulin and glucose. The coagulation profile should be followed to assess for the presence and severity of DIC.

Outcomes and Prevention of Malignant Hyperthermia

Several measures can be taken to prevent the occurrence of MH or limit the severity of the syndrome. The preoperative history may suggest a family history of anesthetic problems or neuromuscular disorders. Known MH triggers should be avoided in known susceptible individuals. Temperature and end-tidal CO2 monitoring should be used during all general anesthesia procedures lasting longer than 30 minutes. Masseter muscle rigidity and increases in heart rate, CO2 levels, and temperature should be evaluated as possible signs of MH. Dantrolene should be readily available in adequate doses. Prophylactic administration of dantrolene is not recommended.

The Malignant Hyperthermia Association of the United States provides a hot line for assistance in managing MH (1-800-MH-HYPER, 1-800-644-9737, or 1-315-464-7079 if outside the United States). The organization also maintains a Web site with useful information online (http://www.mhaus.org).

The mortality rate from MH, which was 50% to 70% decades ago, has decreased to lower than 10% because it is more appropriately recognized and treated. Death may result early in the clinical course from hyperkalemia, acidosis, or hypotension. Later deaths are often related to DIC, renal failure, and multiple organ dysfunction.

Neuroleptic malignant syndrome (NMS) is an idiosyncratic reaction, usually to neuroleptic drugs, characterized by hyperthermia, muscle rigidity, mental status changes, autonomic dysfunction, and rhabdomyolysis. It may occur in up to 1% of all patients on neuroleptic agents and affects males more than females and the young more than the old.30 The pathogenesis of NMS is unknown but is thought to be related to CNS dopamine-2 receptor antagonism or dopamine deficiency in the basal ganglia and hypothalamus resulting in altered temperature set point.31

Triggers of Neuroleptic Malignant Syndrome

Most cases of NMS have been associated with high-potency neuroleptics such as haloperidol and thiothixene. However, the list of potential triggers includes butyrophenones (e.g., haloperidol), phenothiazines (e.g., chlorpromazine and fluphenazine), thioxanthenes (e.g., thiothixene), dopamine-depleting agents (e.g., tetrabenazine), dibenzoxazepines (e.g., loxapine), and withdrawal of levodopa/carbidopa or amantadine. The newer atypical antipsychotic drugs such as clozapine, risperidone, olanzapine, ziprasidone and quetiapine have also been reported to induce NMS. NMS can be associated with antiemetics (prochlorperazine), peristaltic agents (metoclopramide), anesthetics (droperidol), and sedatives (promethazine).32 Rechallenge with the inciting drug may not result in recurrence of NMS. Other factors suggested to contribute to the development of NMS include lithium therapy, ambient heat, dehydration, psychomotor agitation, and underlying brain injury.33,34

Clinical Manifestations

NMS usually occurs 3 to 9 days after initiating a neuroleptic agent or changing the dose. The reaction is not related to dose and may occur after a single dose. The syndrome may last for a period of 1 to 3 weeks, especially with depot drug forms. A similar onset occurs with dose reduction or withdrawal of dopaminergic agents in patients with Parkinson disease. The onset of symptoms can be insidious or fulminant. Symptoms often begin with mental status changes followed in sequence by muscle rigidity, hyperthermia, and autonomic dysfunction, but variability exists.35 Hyperthermia is universally present, and the average maximum temperature is 39.9°C (103.8°F).36,37 However, NMS has been reported to occur without temperature elevation.38 Autonomic dysfunction includes tachycardia, diaphoresis, blood pressure instability, and arrhythmias. Autonomic dysfunction may precede changes in muscle tone. A general increase in muscle tone, “lead pipe” rigidity, or tremors occurs in more than 90% of patients. Early manifestations of changes in muscle tone include dysphagia, dysarthria, or dystonia that may be mistaken for extrapyramidal side effects of the drug. Altered mental status occurs in 75% of patients and can range from agitation to coma. The rigidity, tremors, and confusion of NMS may be attributed to the underlying disease in patients with Parkinson disease and delay the diagnosis. Rhabdomyolysis occurs frequently.

Laboratory findings include elevated creatine kinase levels and myoglobinuria. White blood cell counts are often increased (10,000 to 40,000/mm3) and may demonstrate a left shift.30 DIC has also been reported. Volume depletion or renal injury from rhabdomyolysis results in elevated levels of serum urea nitrogen and creatinine. Significant rhabdomyolysis may lead to serious electrolyte abnormalities.

Various diagnostic criteria have been proposed (Table 111-2), but NMS remains a clinical diagnosis based on exposure to neuroleptic agents or other dopamine antagonists in association with characteristic clinical manifestations.

Treatment of Neuroleptic Malignant Syndrome

Recommendations for treatment of NMS are based primarily on case reports and retrospective analyses because no controlled trials have been conducted in humans and no animal model exists. The patient should be admitted to an intensive care unit, and the precipitating medication should be discontinued. Treatment then involves three aspects: stopping thermogenesis, repletion of dopamine in the CNS, and general support.32 Specific therapy should be individualized to each patient. The Neuroleptic Malignant Syndrome Information Service (http://www.nmsis.org) maintains a hotline for medical professionals (1-888-667-8367) if assistance is needed. Dantrolene is the most effective agent for decreasing muscle rigidity and temperature, although its role in NMS is less well defined than in MH. It can be given in the same doses as described for MH. Neuromuscular blockers and sedation may be infrequently needed for rigidity refractory to dantrolene. Dopamine agonists have been reported to have beneficial effects in NMS,39,40 but results have been inconsistent.41 These drugs include bromocriptine (2.5 to 5 mg orally three times daily, <30 mg/day), amantadine (100 mg orally three times daily), and levodopa/carbidopa. In severe cases, use of all three dopamine agonists may be considered. Benzodiazepines (lorazepam 1 to 2 mg every 8 hours) may be helpful in catatonia and for control of agitation. Electroconvulsive therapy has been used successfully in NMS, but indications are not well established. It may be considered when the clinical presentation overlaps with lethal catatonia.32,42 Supportive therapy is crucial to successful management of NMS because patients typically die of complications such as arrhythmias or aspiration. Intravascular volume should be optimized to replace increased insensible losses and maintain renal blood flow and urine output. Tachycardia and hypertension may respond to β blockers. External cooling may be required, and prophylaxis for venous thromboembolism should be instituted. Complications may include respiratory failure, cardiovascular collapse, renal failure, arrhythmias, or thromboembolism. Mortality rates are lower than 10% if recognition is prompt and appropriate treatment provided.