Endogenous heat production during exertion ranges from 300 to 900 kcal per hour. Even in conditions favoring the maximal evaporation of sweat, only 500 to 600 kcal per hour of heat may be lost. Endogenous heat production may also be increased by fever, thyrotoxicosis, or the hyperactivity associated with amphetamine and hallucinogen use. In these conditions of increased thermogenesis, especially during maximal exercise, a healthy individual with intact regulatory mechanisms may develop hyperthermia.

Schizophrenic, comatose, senile, or mentally deficient patients are at increased risk of heat stroke when ambient temperatures are high, owing to impaired voluntary control [5,6]. These patients may fail to perceive a temperature rise and take appropriate action. Impermeable clothing in hot environments has a great reduction in evaporative heat loss and individuals may suffer heat stroke [7,8].

Acclimatization increases heat tolerance by increasing cardiac output; decreasing peak heart rate; and increasing stroke volume. This lowers the threshold necessary to induce sweating; increases the volume of sweating; and, via an increase in aldosterone, expands extracellular volume and minimizes sweat sodium loss [9,10]. However, unacclimatized individuals who do not mount an adaptive response are at increased risk of suffering exertional heat stroke [11].

Dehydration and impaired cardiovascular performance increases the risk of heat stroke due to a decrease in skin or muscle blood flow, thus decreasing the movement of heat from the core to the environment [10,12]. Hypokalemia increases the risk of heat stroke by decreasing muscle blood flow, impairing cardiovascular performance, and possibly decreasing sweat gland function [9,10]. Adequate fluid intake and maintenance of a normal vascular volume prevents heat stroke. Heat load places a stress on the cardiovascular system and produces hyperthermia in patients with cardiovascular dysfunction. In one report, 75% of patients with compensated cardiac failure developed overt heart failure and temperatures up to 38.0°C after as little as 4 hours’ exposure to temperatures of 32.2°C. Respiratory rate, blood pressure, and central venous pressure (CVP) also tended to rise [13].

Many drugs are known to predispose to heat stroke. Anticholinergic drugs such as phenothiazines, butyrophenones, thiothixenes, and anti-Parkinson’s medications reduce sweat activity [14]). Barbiturate overdose may produce sweat gland necrosis [10]. Diuretics promote dehydration and hypokalemia. Beta-blockers may increase the risk of heat stroke because of cardiodepression. Alcohol consumption may increase the risk of heat stroke 15-fold because of dehydration secondary to antidiuretic hormone inhibition and inappropriate vasodilation [6].

Skin disorders that impair sweat gland function, such as cystic fibrosis and chronic idiopathic anhydrosis, predispose to heat stroke [15]. Hypothalamic lesions impair thermoregulation. During the early stages of heat stroke, the hypothalamus regulates autonomic responses to limit hyperthermia to occur. In the later stages, after thermal toxicity has occurred, hypothalamic regulation is impaired [16]. Anhydrosis has been reported in up to 100% of heat stroke victims in some series [17]. The hypothalamic set point may be elevated. The exact cause of hypohidrosis remains unclear and may reflect hypothalamic dysfunction or only the secondary effects of dehydration and cardiovascular collapse. Electron microscopic studies of eccrine sweat glands in a patient with fatal exertional heat stroke show changes suggestive of sweat gland fatigue [18]. Heat stroke can, however, occur in individuals who perspire profusely, indicating that sweat gland malfunction is not the only factor contributing to the pathogenesis of the syndrome.

The increased risk of heat stroke in the elderly is predominantly due to a decreased ability to sweat and a compromised cardiovascular response to heat exposure when compared with younger individuals [8,19]. In one report, 84% of elderly patients showed no evidence of sweating at the time heat stroke was diagnosed [20]. Elderly patients are more likely to have deficient voluntary control, poor acclimatization, and they take drugs that adversely affect thermoregulation.

Muscle degeneration and necrosis occur as a direct result of high temperatures. Muscle damage is more severe in exertional heat stroke owing to the local increases in heat, hypoxia, and metabolic acidosis associated with exertion. Significant muscle enzyme elevation and severe rhabdomyolysis are extremely common in exertional heat stroke [12,25,26] but rare in classic heat stroke [27].

Cardiac output is increased [28] due to increased demands and low peripheral vascular resistance secondary to vasodilation and dehydration. Dehydration frequently results from sweat rates that may easily reach 1.5 to 2.0 L per hour during episodes of heat stroke [29]. CVP is initially elevated [30].

Hypotension occurs commonly as a result of high-output failure or temperature-induced myocardial hemorrhage and necrosis with subsequent cardiac depression and failure [9,12,31]. Tachyarrhythmias are frequent. Postmortem specimens show focal myocytolysis, myocyte necrosis, and hemorrhage in subepicardial, intramuscular, subendocardial, or intravalvular tissues [32].

Direct thermal toxicity to brain and spinal cord rapidly produces cell death, cerebral edema, and local hemorrhage. These may lead to profound stupor or coma, almost universal features of all the hyperthermic syndromes. Seizures secondary to edema and hemorrhage are not uncommon. Because Purkinje cells of the cerebellum are particularly sensitive to the toxic effects of high temperatures, ataxia, dysmetria, and dysarthria may be seen acutely and in survivors of hyperthermia [10,33]. Progressive cerebellar atrophy has been documented by computed tomography and magnetic resonance imaging [34]. Lumbar punctures in classic and exertional heat stroke may reveal increased protein levels, xanthochromia, and a slight lymphocytic pleocytosis [12,20]. Survivors of severe heat stroke may show premature cataract formation, considered to be secondary to dehydration [35]. Up to 33% of survivors of heat stroke have at least moderate neurologic impairment after discharge from the hospital [36].

Renal damage occurs in nearly all hyperthermic patients; it is potentiated by dehydration, cardiovascular collapse, and rhabdomyolysis. In classic heat stroke, acute renal failure occurs on average in 5% of patients as a result of dehydration [9]. In exertional heat stroke, acute renal failure occurs in up to 35% of cases [9,31]. Dehydration, pigment load, hypoperfusion, and urate nephropathy are thought to contribute to a clinical picture of acute tubular necrosis [31]. Other features include low serum osmolarity, moderate proteinuria, active sediment, and
characteristic machine-oil appearance of the urine. In one series, the incidence of acute tubular necrosis increased with survival time [32]. Hypocalcemia and creatine phosphokinase values above 10,000 U per L increase the risk of acute renal failure [37]. Respiratory alkalosis is common in mild hyperthermia with metabolic acidosis predominating at temperatures greater than 41°C [24].

The combination of direct thermotoxicity and relative hypoperfusion of the intestines during hyperthermia leads to ischemic intestinal ulcerations that may result in frank bleeding [9]. Hepatic necrosis and cholestasis occurs 2 to 3 days after hyperthermic insult, and 5% to 10% of cases result in death [10].

White blood cell counts are elevated owing to catecholamine release and hemoconcentration. Anemia and a bleeding diathesis [29] are present due to (a) direct inactivation of platelets and bleeding factors by the heat, (b) a decrease in coagulation factor synthesis owing to liver failure, (c) a decrease in platelet and megakaryocyte counts, (d) platelet aggregation [38], and (e) disseminated intravascular coagulation (DIC). Megakaryocyte counts are reduced in up to 50% of specimens, and surviving megakaryocytes are morphologically abnormal [32]. DIC is present in most cases of fatal hyperthermia [32,39], most frequently appearing on the 2nd or 3rd day after hyperthermic insult. It is thought to be due to activation of the clotting cascade by vascular endothelial damage and generalized cell necrosis [40]. In cases of DIC, cardiac, CNS, pulmonary, gastrointestinal (GI) tract, and renal complications are exacerbated. An increase in blood viscosity of up to 24% has been postulated to facilitate thromboses [41].

Hypoglycemia may occur in severe exertional heat stroke due to metabolic exhaustion [26]. In milder heat stroke, hyperglycemia and elevations of serum cortisol have been reported [42]. Although in autopsies the adrenal glands frequently show pericortical hemorrhages, survivors show little evidence of adrenal dysfunction [22,31]. Growth hormone and aldosterone levels actually increase abruptly during severe, acute heat exposure and are thought to act to preserve volume.

Hyperthermia produces frequent imbalances in potassium, sodium, phosphate, and calcium levels [29,43]. In heat stroke, sweating involves the active excretion of potassium from the body, producing normal to low serum potassium levels and slightly decreased total body potassium concentrations. In cases of exertional heat stroke with severe cell injury, potassium levels may be extremely elevated owing to cell lysis. Although mild hypophosphatemia occurs frequently as a result of intracellular trapping and possible parathyroid hormone resistance, phosphate levels may decrease to less than 1 mg per 100 mL in cases of hyperthermia with severe rhabdomyolysis [43]. Calcium values may fall 2 to 3 days after cellular injury owing to intracellular precipitation. In patients with severe tissue injury rebound, hypercalcemia may occur 2 to 3 weeks after hyperthermia as a result of parathyroid hormone activation [43].

Direct thermal injury to the pulmonary vascular endothelium may lead to cor pulmonale or acute respiratory distress syndrome. This and the tendency toward myocardial dysfunction make pulmonary edema common. Increased oxygen demands and acidosis frequently produce a respiratory alkalosis. Metabolic acidosis is, however, the most common acid–base disorder [44].

Primary therapy includes cooling and decreasing thermogenesis. Some cooling may be achieved in the field by moving the victim to a shaded, cooler area; removing the clothes; constantly wetting the skin; and fanning or transport in an open vehicle to create a breeze. Once the victim reaches hospital, cooling and subsequent supportive care are best provided in an intensive care setting.

Cooling by evaporative or direct external methods has proved effective. Evaporative cooling methods involve placing a nude patient in a cool room, wetting the skin with water, and encouraging evaporation by using fans. In one specially designed evaporative cooling unit, patients were sprayed with 15°C water and their skin fanned at 30 times per minute with air heated to 45°C to 48°C. Temperature reduction was rapid and mortality was 11% [57]. There was no mortality in 25 patients with nonexertional heat stroke treated with cooling by covering with a cool, wet, 20°C sheet and fanning with two 35-cm electric fans. Fanning was adjusted to maintain skin temperature at 30°C to 32°C; skin temperature fell 1°C every 11 minutes [58]. In 14 patients with nonexertional heat stroke, there was one death when evaporative/convective cooling was employed. The median time to return to temperature less than 39.4°C was 60 minutes.

Direct external cooling involves immersing the patient in ice water or packing the patient in ice. Ice water immersion with massage has been effective with little complication [59]. Colder water cools more rapidly (up to 0.35°C per minute), with one study demonstrating that 2°C water cooled volunteers twice as rapidly than 8°C water [60]. Because cold skin temperatures produce vasoconstriction, however, constant massage may be necessary to allow circulation to carry heat from the core. Direct external cooling is highly effective but makes patient monitoring and management extremely inconvenient. Therefore, some authors advocate evaporative cooling as a safer cooling method in patients at high risk of cardiovascular collapse [52]. As comparative studies of cooling techniques use different water temperatures for immersion and different evaporative cooling protocols, there is no consensus on which technique is superior. In most cases, treatment will be determined by what resources are immediately available. The Israeli Defense Forces protocol involves moving the collapsed patient to the shade, removing clothing, splashing the skin with water while fanning, and transport to hospital in an open vehicle. These measures yielded a cooling rate of 0.11°C per minute [61]. The US Marine Corps protocol calls for covering the patient with sheets covered with ice and then fanning the patient. This has had no mortalities in 200 cases and has reduced temperatures to below 39°C in 10 to 40 minutes [62].

In rare instances in which evaporative and direct external cooling methods fail to reduce the temperature, peritoneal lavage with iced saline cooled to 20°C or 9°C, gastric lavage, or hemodialysis or cardiopulmonary bypass with external cooling of the blood may be necessary to reduce the temperature. Temperature should be continuously monitored and cooling stopped as it approaches 39°C. Although chlorpromazine in an intravenous (IV) dose of 10 to 25 mg has been advocated to prevent shivering during cooling, it is usually unnecessary. Cooling blankets, although commonly used, are extremely ineffective and are not recommended [63]. Dantrolene has been shown to be ineffective in reducing hospitalization rate in heat stroke [64], and although it may improve cooling rate, it did not alter mortality [65].

Arrhythmias, metabolic acidosis, and cardiogenic failure complicate the early management of hyperthermic crises. Supraventricular tachyarrhythmias usually require no treatment because they respond to restoration of normal temperature and metabolism. Digitalis should be avoided owing to the likelihood of hyperkalemia.

Hypotension should be treated initially with normal saline and, if necessary, isoproterenol. Dopaminergic and α-agonists should be avoided because they tend to produce peripheral vasoconstriction. Volume expansion with dextran is contraindicated owing to its anticoagulating effect. Pulmonary artery and arterial catheter monitoring may be helpful in the management of hypotension because patients frequently have low peripheral resistance, dehydration, and impaired cardiac function and are at a high risk for congestive heart and renal failure. As 64% of patients may have a normal central venous pressure before resuscitation, volume expansion in most cases should be guided by intravascular pressure monitoring where available [66]. Seizures, quite common in heat stroke, usually respond to diazepam.

Blood gas status should be determined early in treatment. Blood gases drawn at temperatures above 39°C should be corrected for temperature, although to our knowledge no studies have demonstrated that this is clinically necessary. The solubility of oxygen and carbon dioxide increases as blood drawn from the patient is cooled to 37°C for analysis. This lowers the carbon dioxide and oxygen tensions and elevates the pH when compared with values present in the patient. Therefore, the patient is more acidotic and less hypoxic than the uncorrected values indicate. Normal values of intracellular pH and changes on the body’s buffering system in hyperthermia have been poorly described. Because normal values for blood gases in hyperthermic patients are unavailable, by convention the blood gas values are corrected for temperature, using any reliable nomogram, and clinical decisions are made as if the patient were euthermic [67,68,69]. The following approximate corrections have been used: for each 1°C that the patient’s temperature is above 37°C, the oxygen tension is increased by 7.2%, carbon dioxide (CO₂) tension increased by 4.4%, and pH is lowered by 0.015 units. More research is needed before definite
conclusions can be made. Nevertheless, 100% oxygen should be delivered until adequate oxygenation is ensured. Bicarbonate should be administered, guided by frequently obtained arterial blood gas values. The base deficit is frequently large, and up to 30 g of bicarbonate has been required for correction. Comatose patients should have prophylactic intubation to protect their airways from aspiration.

Urine output should be closely monitored with an indwelling bladder catheter. Patients should be routinely given 1 to 2 mg per kg of mannitol over 15 to 20 minutes to promote continued urine flow and possibly decrease cerebral edema. Continuous urine output should then be maintained with intermittent doses of furosemide. In all cases of hyperthermia, serum potassium levels should be closely followed. In cases of oliguria or potential renal failure, polystyrene sulfonate should be given early because hyperkalemia frequently increases.

Moderate-to-severe liver failure is common, may prolong illness, and, in combination with renal failure, may make administration of several drugs difficult or impossible. Although no clinical data are yet available, histamine receptor type 2 (H₂)–blocking drugs or proton pump inhibitors given prophylactically may decrease the incidence of GI tract bleeding.

The occurrence of DIC greatly affects mortality: Most patients who die of heat stroke have evidence of DIC [70]. Coagulation parameters such as prothrombin time, partial thromboplastin time, platelet count, and fibrinogen should be carefully followed. Should DIC occur, traditional recommendations for treatment should be followed (see Chapter 108).

The use of steroids and prophylactic antibiotics are not recommended [20,26]. Steroids are of no known benefit in heat stroke. Infection has not been reported as a major cause of morbidity and mortality in hyperthermia, and antibiotics are associated with superinfections.