30: Thermoregulatory Principles

Despite exposure to wide fluctuations of environmental temperatures, human body temperature is maintained within a narrow range.^17,126 Elevation or depression of body temperature occurs when (1) thermoregulatory mechanisms are overwhelmed by exposure to extremes of environmental heat or cold; (2) endogenous heat production is either inadequate, resulting in hypothermia, or exceeds the physiologic capacity for dissipation, resulting in hyperthermia; or (3) disease processes or xenobiotic effects interfere with normal thermoregulatory responses to heat or cold exposure.

Heat is transferred to or away from the body through radiation, conduction, convection, and evaporation. Radiation involves the transfer of heat from a body to the environment and from warm objects in the environment, for example, from the sun to a body. Conduction involves the transfer of heat to solid or liquid media in direct contact with the body. Water immersion conducts significant amounts of heat away from the body. This effect facilitates cooling in a swimming pool on a hot summer day or may lead to hypothermia despite moderate ambient temperatures on a rainy day. The amount of heat lost through conduction and radiation depends on the temperature gradient between the skin and its surroundings; cutaneous blood flow; and insulation such as subcutaneous fat, hair, clothing, or fur in lower animals.¹⁴³ In the respiratory tract, heat is lost by conduction to water vapor or gas. In animals unable to sweat, this represents the primary method of heat loss. The amount of heat lost through the respiratory tract depends on the temperature gradient between inspired air and the environment and the rate and depth of breathing.¹⁴³Convection is the transfer of heat to the air surrounding the body. Wind velocity and ambient air temperature are the major determinants of convective heat loss. Evaporation is the process of vaporization of water, or sweat. Large amounts of heat are dissipated from the skin during this process, resulting in cooling. Ambient temperature, rate of sweating, air velocity, and relative humidity are important factors in determining how much heat is lost through evaporation. On a very hot and humid day, sweat may pour off an exercising person who rather than evaporating and initiating heat loss is accomplishing little heat loss. In very warm environments, thermal gradients may be reversed, leading to transfer of heat to the body by radiation, conduction, or convection.¹⁵⁶

In a normal human, stimulation of peripheral and hypothalamic temperature-sensitive neurons results in autonomic, somatic, and behavioral responses that lead to the dissipation or conservation of heat. Thermoregulation is the complex physiologic process that serves to maintain hypothalamic temperature within a narrow range of 98.6 ± 0.8°F (37 ± 0.4°C), known as the set point.¹²⁶ This hypothalamic set point is influenced by ­factors such as diurnal variation, the menstrual cycle, and others. Maintaining, raising, or lowering the set point results in many outwardly visible physiologic manifestations of thermoregulation such as sweating, shivering, flushing, or panting. In the central nervous system (CNS), thermosensitive neurons are located predominantly in the preoptic area of the anterior hypothalamus, but to a lesser extent in the posterior hypothalamus. These neurons may be divided into those that are warm sensitive, cold sensitive, or temperature insensitive. Approximately 30% of preoptic neurons are warm sensitive. These increase their firing rate during warming and decrease their firing rate during cooling.³⁰ Warming of the hypothalamus in conscious animals results in vasodilation, hyperventilation, salivation, and increases in evaporative water loss, as well as a reduction of cold-induced shivering and vasoconstriction.¹²⁶ Cooling of the hypothalamus in conscious animals causes shivering, vasoconstriction, and increased metabolic rate even if the environment is hot.¹¹⁷ How these temperature-sensitive neurons of the hypothalamus detect temperature changes and effect neuronal transmission is unclear. Altered action potential initiation and propagation caused by temperature-dependent membrane potential changes associated with the ratios of Na⁺ to Ca²⁺ ions that alter neuronal excitability and neurotransmitter release, or effects on the Na⁺-K⁺-ATPase (adenosine triphosphatase) pump.¹⁴³ Xenobiotics that increase intracellular cyclic adenosine monophosphate (cAMP) concentrations increase the thermosensitivity of warm-sensitive neurons.³⁰ In the brainstem, warm- and cold-sensitive neurons are located in the medullary reticular formation, where information from cutaneous receptors, spinal cord, and preoptic area of the anterior hypothalamus is integrated.¹³²

The spinal cord is thermosensitive. Heat and cold sensitive ascending spinal impulses are conducted in the spinothalamic tract. As in the hypothalamus, local heating or cooling of the spinal cord results in thermoregulatory responses.¹²⁶ In addition to the hypothalamus, brainstem, and spinal cord, there is evidence of thermosensitivity in the deep abdominal viscera.^113,126,228 Intraabdominal heating or cooling results in thermoregulatory responses. Cold and warm sensitive afferent impulses can be recorded from the splanchnic nerves in animals.^113,230 Finally, the skin also contains heat and cold thermosensitive neurons. Whereas cold receptors are free nerve endings that protrude into the basal epidermis, warm sensitive receptors protrude into the dermis.^125,127 Cutaneous thermoreceptor output is affected by the absolute temperature of the skin, rate of temperature change, and area of stimulation.¹²⁶ Cutaneous cold receptors are A-δ and C nociceptor afferent fibers. A δ fibers are ­small-diameter, thinly myelinated fibers that conduct at 5 to 30 m/sec, and C fibers are small-diameter, unmyelinated fibers that conduct at 0.5 to 2 m/sec.¹²¹ Afferents from heat receptors are primarily C fibers. Cutaneous thermoreceptive neurons respond to external temperature change as well as rate of temperature change, sending early warning to the CNS via afferent impulses, allowing rapid and transient thermoregulatory responses before brain ­temperature changes (Fig. 30–1).

Vasomotor and Sweat Gland Function

Vasomotor responses to thermoregulatory input differ according to ­location. The normal thermoregulatory response to heat stress is mediated primarily by heat-sensitive neurons in the hypothalamus. Increased body-core temperature results in active vasodilation in the extremities and is under noradrenergic control; increasing sympathetic stimulation results in vasoconstriction, and decreasing sympathetic control results in ­vasodilation. Vasodilation in the head, trunk, and proximal limbs is not a result of decreased sympathetic tone; instead, it is a result of an active process that is under the influence of cholinergic sudomotor nerves and local effects of temperature on venomotor tone. Sweat glands release local transmitters, such as vasoactive intestinal polypeptide (VIP) or bradykinins, and vasodilation results. Areas of the body such as the forehead, where sweating is most prominent during heat stress, correspond to areas where active vasodilation is greatest. The neurotransmitters involved in the regulation of relationships between vasodilation and sweating as a response to heat stress are not fully elucidated, but animal evidence suggests the presence of specific vasodilator nerves.¹²⁶

Sweat glands are controlled by postganglionic nerve fibers, which are cholinergic, and large amounts of acetylcholinesterase as well as other peptides are involved in neural transmission.^125,126

Neurotransmitters and Thermoregulation

The neurotransmitters involved in thermoregulation include serotonin, ­norepinephrine, acetylcholine, dopamine, prostaglandins, β-endorphins, and intrinsic hypothalamic peptides such as arginine vasopressin, adrenocorticotropic hormone, thyrotropin-releasing hormone, and melanocyte–stimulating hormone.^51,217 Studies on the effects of individual neurotransmitters in thermoregulation yield contradictory results, depending on the animal species and the route of administration of the exogenous neurotransmitter. Refinements in techniques of microinjection of neurotransmitters into the hypothalamus of animals, rather than intraventricular instillation, have elucidated microanatomic sites where neurotransmitters are active. More research is needed, however, because interspecies variations and theoretical differences in response to exogenous versus endogenous peptides make this area of study complex.

Apomorphine is a mixed dopamine agonist that causes hypothermia in animals; studies using selective D₁- and D₂-receptor agonists and antagonists suggest that the hypothermic effect of apomorphine is a result of its effects on D₂ receptors, with some modulation by D₁ receptors in the hypothalamus.¹⁹⁵ Stimulation of D₂ receptors appears to mediate the hypothermia induced by the peptide sauvagine.³³ Stimulation of D₃ by specific agonists caused hypothermia in an animal model.^196,197 There appears to be a link between dopamine D₂ receptors and norepinephrine receptors in the hypothalamus, perhaps leading to vasodilation and hypothermia. The effect of clozapine in producing hypothermia in rats is caused by D₁ and D₃ stimulation.^196,241 Lesser known peptides appear to be involved in ­thermoregulation. For example, neuropeptide Y is an amino acid neurotransmitter that occurs in high concentrations in the preoptic area of the anterior ­hypothalamus. Administration of neuropeptide Y caused a reduction in core temperature when administered with adrenergic receptor antagonists such as prazosin, an α₁-adrenergic antagonist; propranolol, a β-adrenergic antagonist; and clonidine, a central α₂-adrenergic agonist.^84,239 Studies on muscarinic receptors suggest the involvement of muscarinic M₂ and M₃ receptors in the production of hypothermia when agonists to these receptors are administered centrally.²⁴² Blockers of ATP–sensitive K⁺ channels can reverse the effect of cholinomimetic drugs in producing hypothermia.²²⁵

Many xenobiotics have pharmacologic effects that interfere with thermoregulatory responses (Tables 30–1 and 30–2).^180,182,281α-Adrenergic agonists prevent vasodilation in response to heat stress. Increased endogenous heat production in the setting of increased motor activity also occurs in patients poisoned with cocaine or amphetamines. Life-threatening hyperthermia is associated with the use of these xenobiotics. Whereas adrenergic antagonists and calcium channel blockers diminish the cardiac reserve available to compensate for heat-induced vasodilation, diuretics decrease cardiac reserve through their effects on intravascular volume.⁶⁴β-Adrenergic antagonists also interfere with the capacity to maintain normothermia under conditions of cold stress, possibly related to their interference with the mobilization of substrates required for ­thermogenesis.^126,182 Opioids and diverse sedative–hypnotics depress hypothalamic function and predispose to hypothermia in the overdose setting.⁸⁶ Carbon monoxide poisoning must also be considered in ­hypothermic patients. Organic phosphorous insecticides and other xenobiotics that cause cholinergic stimulation cause hypothermia by stimulation of inappropriate sweating and possibly through depression of the endogenous use of calorigenic substrates.¹⁸² Xenobiotics with anticholinergic effects decrease sweating and predispose to hyperthermia during environmental heat exposure or exercise. Phenothiazines appear to interfere with normal response to both heat and cold. Severe hyperthermia associated with the absence of sweating is frequently described in patients using phenothiazines and may be a consequence of their anticholinergic effects.^243,297 Effects on cold tolerance are attributed to their α-adrenergic antagonist effects, which prevent vasoconstriction in response to cold stress.¹⁸¹ In addition, hyperthermia associated with severe extrapyramidal rigidity may occur in patients taking antipsychotics.¹⁷³ This rigidity is attributed to the dopamine-blocking effects of this class of drugs.

Ethanol is the xenobiotic most commonly related to the occurrence of hypothermia in an urban setting.^62,288,289 The mechanism by which ethanol predisposes to hypothermia is said to be by virtue of its effects on CNS depression, vasodilation, and blunting of behavioral responses to cold. However, thermoregulatory dysfunction associated with ethanol intoxication is undoubtedly more complex.

In animal models, ethanol leads to hypothermia, the extent of which is partly dependent on ambient temperature.^211,231,232 In mice, as the dose of ethanol increased, body temperature decreased, and the rate of this decline in body temperature was faster at higher ethanol doses.²⁰⁶ The decline in body temperature could be reversed by increasing ambient temperature; increasing ambient temperature to 96.8°F (36°C) caused an immediate rise in the body temperature.²⁰⁶ The poikilothermic effect of ethanol was not a result of hypoglycemia. Poikilothermia is the variation in body temperature greater than ±3.6°F (±2°C) on exposure to environmental temperature changes. Rats treated with equipotent amounts of sodium pentobarbital showed the same effects on body temperature as rats treated with ethanol, suggesting a similar central mechanism of CNS depression resulting in altered thermoregulation.²⁰⁶

Numerous mechanisms are involved in the ethanol-induced depression of CNS function.²³⁶ Genetic factors influence the role of ethanol in the production of hypothermia. Mice can be selectively bred for genetic sensitivity or insensitivity to acute ethanol-induced hypothermia, and the differences appear to be mediated by the serotonergic systems.^{87,101,200,206} Cyclo His-Pro DKP, another neurotransmitter that is found in many animal species, acts at the preoptic-anterior hypothalamus to modulate body temperature.^41,136 Exogenous administration of this neuropeptide produced a dose-dependent decrease in ethanol-induced hypothermia. Attenuation of hypothermia resulted from passive immunization with CHP antibody.^41,136 Ethanol effects may be mediated through modulation of endogenous opioid peptides because high-dose (10 mg/kg) naloxone reverses ethanol-induced hypothermia in animals.²²¹

Pharmacokinetic characteristics of ethanol metabolism change in the presence of hypothermia. Hypothermic piglets infused with ethanol showed slower ethanol metabolism and a smaller volume of distribution (Vd) and, as a result, higher ethanol concentrations than normothermic control piglets. Ethanol elimination and metabolism decreased as temperature fell.¹⁶³

Tolerance develops to the effect of ethanol in producing hypothermia in all species.^89,211 The degree of tolerance is proportional to the dose and duration of treatment with ethanol and is not explained by the increased rate of metabolism with chronic exposure.¹⁴³ Age is a factor in the development of tolerance; older animals do not display the same degree of tolerance to the hypothermic effects of chronic ethanol administration as do younger animals.^203,220,296 The development of tolerance to ethanol-induced hypothermia is affected by genetic factors. Experimentally, tolerance to ethanol-induced hypothermia increases the incorporation of certain amino acids into proteins in the rat brain. The formation of new proteins in ethanol-tolerant rats suggests stimulation of gene expression related to the tolerant state.^143,284 Deficits in N-methyl-d-aspartate (NMDA) receptor systems may also be implicated in the development of ethanol tolerance. In addition, altered nicotinamide adenine dinucleotide (NADH) oxidation to NAD⁺, diminished blood flow to the liver, or slowing of metabolism through the microsomal enzyme system may be involved.²³⁶

Hypothermia alters the breath-ethanol partition in the alveolus, and the temperature of expired breath alters breath-ethanol analysis results. In patients with mild hypothermia, ethanol-breath analysis results in lower values by 7.3% per degree centigrade (or 1.8°F) decrease in body temperature.⁹² Whether breath-ethanol analysis is also affected by hyperthermia remains to be studied.⁹²

Many disease processes interfere with normal thermoregulation, limiting an individual’s capacity to prevent hypothermia or hyperthermia. Extensive dermatologic disease or cutaneous burns impair sweating and vasomotor responses to heat stress.³⁶ Patients with autonomic disturbances such as diabetes mellitus or peripheral vascular disease also have altered vasomotor responses that impair vasodilation and sweating.²²⁹ Extensive surgical dressings may preclude the evaporation of sweat in an otherwise normal patient. Heat stressed persons with poor cardiac reserve may not be able to sustain skin blood flow rates high enough to maintain normothermia.^76,264 Intense motor activity may lead to excessive heat production in patients with Parkinson disease or hyperthyroidism. Patients with agitated delirium or seizures also have significantly elevated rates of endogenous heat production. Hypothalamic injury caused by cerebrovascular accidents, trauma, or infection may disturb thermoregulation.^75,177 Hypothalamic dysfunction can lead to high, unremitting fevers and insufficient stimulation of heat loss mechanisms such as sweating. Hypothalamic damage may predispose to hypothermia by interference with centrally mediated heat conservation.^{75,177,244,245} Fever, the normal response to stimulation of the hypothalamus by pyrogens, results in an elevated physiologic temperature set point and is a disadvantage in the heat-stressed individual.¹²⁶

Epidemiology

Hypothermia is defined as a lowering of the core body temperature to below 95°F (<35°C). Between 1999 and 2002, 4607 people had hypothermia-related diagnoses listed on their death certificates as the underlying cause of death.⁴⁶ Most of these, 2622, were caused by exposure to excessive cold; in the remainder, hypothermia resulted from some reason other than exposure, such as medical illness^{43,44,130,159} (Table 30–3).

Most hypothermic deaths occur in the winter months; however, mildly cool environments and windy wet conditions are also frequently associated with hypothermia. From 1999 to 2011, a total of 16,911 deaths in the United States were associated with exposure to excessive natural cold. Alaska, Montana, Wyoming, and New Mexico had the greatest overall death rates from hypothermia. States with milder climates and rapid fluctuations in temperature, such as North and South Carolina, and western states, such as Arizona, with high elevations and cold nighttime temperatures, report hypothermia-related deaths.⁴⁶

Response to Cold

The normal physiologic response to cold is initiated by stimulation of cold-sensitive neurons in the skin, so that the onset of the body response to cold occurs before cooling of central blood. Cold-sensitive neurons in the skin send afferent impulses to the hypothalamus, resulting in shivering and piloerection. Shivering is the main thermoregulatory response to cold in humans, except in neonates, in whom nonshivering thermogenesis prevails. Shivering is initiated in the posterior hypothalamus when impulses from cold-sensitive thermoreceptors are integrated in the anterior hypothalamus and communicated to the posterior hypothalamus or when cold-sensitive neurons in the posterior hypothalamus are activated directly. Efferent stimuli from the posterior hypothalamus travel through the midbrain tegmentum, pons, and lateral medullary reticular formation to the motor pathways of the tectospinal and rubrospinal tracts, resulting in shivering.²² A mechanism of stimulation of shivering that usually occurs later when core temperature drops is the local cooling of the spinal cord, which leads to shivering by increasing excitability of motor neurons.

Heat produced without muscle contraction is known as nonshivering thermogenesis.^34,126 Nonshivering thermogenesis is mediated by the sympathetic nervous system.⁵⁶ Catecholamines activate adenylate cyclase, increasing cAMP, resulting in mobilization of fat and glucose stores (β-adrenergic receptors).^183,238 Nonshivering thermogenesis is blocked by α-adrenergic receptor antagonism and increased by administration of norepinephrine. Brown adipose tissue is the most important site of nonshivering thermogenesis. In humans, brown fat is found primarily in neonates, although in cold-acclimatized people, there may be small amounts found on autopsy.³⁴ Brown adipose tissue functions as a thermoregulatory effector organ, producing heat by the oxidation of fatty acids when the tissue is stimulated by norepinephrine.⁴⁰

In addition to shivering and nonshivering thermogenesis, efferent sympathetic fibers from the hypothalamus stimulate peripheral vasoconstriction (α-adrenergic receptors). Piloerection and vasoconstriction result in decreased heat loss from the body. Intense vasoconstriction shunts blood away from the periphery to the core and antidiuretic hormone antagonism results in increased urine output and hemoconcentration.

Several disease processes commonly result in an inability to maintain a normal body temperature in a cool environment (Table 30–3). Hypothermia may develop in association with sepsis, hypothyroidism, hypoglycemia, uremia, hepatic failure, or poor nutrition.^68,175 Hypothalamic injury may result in chronic poikilothermia.¹⁸¹ Thiamine deficiency adversely affects the hypothalamus, perhaps because of inefficient glucose metabolism, and leads to hypothermia.¹⁶¹ Spinal cord transection above the first thoracic segment interrupts hypothalamic–sympathetic outflow pathways, resulting in hypothermia.²²⁹ Frail elderly adults are at greater risk of ­hypothermia because of decreased vasomotor responses and a decreased capacity to shiver.^56,59 Mentally and physically compromised patients may be unable to make appropriate behavioral responses to hot or cold environments.

Evaluations to determine the presence of underlying diseases are often difficult in a patient with hypothermia.^90,175 The mental status may be ­markedly altered by hypothermia but is not usually abnormal until the temperature falls below 90°F (32.2°C). If normal mental status is not regained when the temperature reaches 90°F (32.2°C) during rewarming, underlying CNS structural, toxic, or metabolic problems must be considered.^90,175,226 Failure of the patient to rewarm quickly suggests the presence of underlying disease⁶⁸ (Fig. 30–2). In one study, whereas hypothermic patients without underlying disease are reported to rewarm at a rate of 1.0 to 3.7°F/h (0.6–2.1°C/h) (average, 2.1°F/h; 1.2°C/h), patients with significant underlying disease (sepsis, gastrointestinal {GI} hemorrhage, diabetic ketoacidosis, pulmonary embolus, myocardial infarction) warmed at a rate of 0.25 to 1.8°F/h (0.1–1.0°C/h) (average, 1°F/h; 0.6°C/h).²⁸⁸

Alteration of Pharmacology in Hypothermia

The pharmacology of certain xenobiotics is altered in the setting of hypothermia. In hypothermic piglets, the Vd and the clearance of fentanyl are decreased.¹⁶³ Similarly, in piglets given gentamicin, the Vd and clearance rate decreased in direct proportion to the decrease in cardiac output and glomerular filtration rate (GFR).¹⁶² Hypothermic puppies given intravenous (IV) lidocaine showed slower rates of disappearance of the drug than when normothermic.²⁰¹ Humans and animals given propranolol showed a reduced Vd and decreased total body clearance, resulting in higher than expected propranolol concentrations.^{35,188,189,209} Decreased hepatic metabolism of propranolol during hypothermia has been shown in vitro.¹⁸⁹ Hypothermia prolongs neuromuscular blockade with d-tubocurarine¹¹⁵ and increases neuromuscular blockade with suxamethonium.²⁹³ Phenobarbital metabolism and Vd decreased with hypothermia in children.¹⁴² The lethal dose of digoxin was doubled in hypothermic dogs.¹⁸ Digoxinlike substances are present during hypothermia.^97,129

Reasons for altered metabolism in hypothermia include delayed distribution of the drug and altered enzyme function with temperature and pH changes. Cardiac output decreases, leading to decreased liver perfusion and decreased delivery of drug to hepatic microsomal enzymes.^{115,145,146, and 147,218} Plasma volume decreases as free water moves intracellularly, causing hemoconcentration and further decreasing organ perfusion.¹¹⁶ Biliary excretion of atropine, procaine, and sulfanilamide decreases in vitro.^{145,146, and 147} The GFR decreases in hypothermia.³¹ In vitro, the activity of metabolic pathways, including acetylation and hydrolysis, decrease with cooling.^145,146

Xenobiotic Metabolism in Therapeutic Hypothermia.

Hypothermiais induced for its neuroprotective effects but requires attention to alterations in pharmacokinetics and pharmacodynamics of xenobiotics administered during hypothermia. Physiological changes during induced hypothermia are similar to those of unintentional hypothermia and include slowed enzymatic reactions, vasoconstriction, decreased ­cardiac output, and hemoconcentration. Studies support a decrease in the Vd of pancuronium, midazolam, morphine, and gentamicin.⁶⁵ Clearance of xenobiotics is affected by organ perfusion, enzyme activity, and xenobiotic characteristics such as the degree of protein binding and the pKa. Hepatic and renal clearance is affected by regional blood flow, which is decreased during hypothermia. In general, the decrease in the Vd and the decrease in clearance result in increased serum xenobiotic concentrations.²³­Experimental studies in animals demonstrate a 25% increase in fentanyl concentrations at a core temperature of 32°C.⁹³ Concurrent ­supportive modalities during hypothermia such as cardiopulmonary bypass or extracorporeal membrane oxygenation (ECMO) further alter the kinetics of xenobiotics during ­hypothermia.²⁹⁰ In neonates, asphyxia treated with induced hypothermia presents the additional complication of rapidly changing neonatal physiology and the effects of supportive measures such as ECMO.⁶⁵

Clinical Findings

The clinical effects of hypothermia are related to the membrane depressant effects of cold, which result in ionic and electrical conduction disturbances in the brain, heart, peripheral nerves, and other major organs (Table 30–4).¹³¹ Cold tissues are protected by decreases in tissue oxygen requirements. As body temperature decreases, metabolic activity declines at a rate of approximately 7% per 1.8°F (1°C).²⁹⁵ This effect provides significant protection to vital organs despite the potentially deleterious effects of membrane suppression.

Effects on the CNS are temperature dependent and predictable. Mild hypothermia (90–95°F; 32.2–35°C) usually results in relatively benign clinical manifestations. Ataxia, clumsiness, slowed response to stimuli, and dysarthria are common.⁹⁰ As cooling continues, the mental status slowly deteriorates. In moderate hypothermia (80–90°F; 27–32.2°C), the patient is usually lethargic but still likely to respond verbally. In severe hypothermia (68–80°F; 20–26.6°C), the patient is unlikely to respond verbally but will react purposefully to noxious stimuli.^90,122 In profound hypothermia (<68°F; <20°C), the patient is unresponsive to stimuli. The pupils may be fixed and dilated and the patient may appear dead.¹²² However, standard criteria for brain death do not apply to hypothermic patients. The hypothermia itself protects against cerebral hypoxic damage.¹³¹ Temperature drop inhibits the release of the excitatory neurotransmitter glutamate and attenuates the release of dopamine in animal models of brain ischemia, suggesting a protective effect of hypothermia in brain injury.³⁹ Cerebrospinal fluid (CSF) glutamate concentrations were lower in patients showing benefit from mild induced hypothermia after brain injury compared with brain-injured patients kept normothermic.¹⁸⁵

Patients have survived with body temperatures as low as 48.2°F (9°C).⁹⁴ Vigorous resuscitation is required for these patients. This approach may lead to hours of cardiopulmonary resuscitation (CPR) of hypothermic patients with ventricular fibrillation, ventricular tachycardia, or asystole but may be ultimately successful in resuscitating patients initially presumed to be dead.²⁶²

For field rescue work, the Swiss distinguish between five stages of hypothermia and provide guidelines for rescue in dangerous environmental conditions. These stages are based on the degree of consciousness, the presence or absence of shivering, cardiac activity, and core temperature.^74,35 The adage that a patient cannot be considered dead until the patient is warm and dead is further refined by the Swiss guidelines for field rescue attempts under avalanche conditions.

The cardiac and hemodynamic effects of cold correlate closely with body temperature. As cooling begins, there is a transient increase in ­cardiac output. Tachycardia develops secondary to shivering and sympathetic stimulation. At about 81°F (27.2°C), shivering ceases. Bradycardia develops with maintenance of a normal cardiac stroke volume.³⁷ This bradycardia is responsible for the decreased myocardial oxygen demand, which may be protective in the setting of hypothermia.³⁷ In profound hypothermia, bradycardia may progress to asystole and death.

Unlike cerebral circulation, in which autoregulation is preserved ­during cooling, coronary autoregulation is disturbed during hypothermia, and myocardial injury may ensue.³⁷ Attempts to maximize myocardial ­oxygenation through administration of oxygen and volume replacement to increase diastolic filling pressures are appropriate.

The initial response to cold is hyperventilation; however, as temperature continues to decrease, hypoventilation develops, which may progress to apnea and death. In animal models, this has been attributed to cold-induced failure of phrenic nerve conduction.¹⁵⁴

The Electrocardiogram

The most common electrocardiographic (ECG) abnormality in hypothermia is generalized, progressive depression of myocardial conduction. PR, QRS, and QT intervals are all prolonged, and increasingly profound hypothermia may lead to gradual progression to asystole.^73,277 Ventricular fibrillation occurs in an irritable myocardium most commonly at temperatures less than 86°F (30°C), resulting in a high O₂ consumption dysrhythmia. Atrial fibrillation is the most common dysrhythmia occurring in the presence of hypothermia.^91,219 Shivering may not be clinically evident, but the characteristic fine muscular tremor frequently produces a mechanical artifact in the baseline of the ECG.⁷⁸ A deflection occurring at the junction of the QRS and ST segment is invariably present in patients with temperatures <86°F (<30°C) (Fig. 30–3). First described in a single patient in 1938, the J-point deflection is commonly known as the Osborn wave.^79,222,273 The J-point deflection, thought to be a “current of injury” associated with CO₂ retention under hypothermic conditions, was believed to be a poor prognostic sign.²²² Subsequent study does not support any prognostic significance because the J-point deflection is invariably found in hypothermic patients when multiple ECG leads are obtained.^{78,79,275,282} The size of the J-point deflection increases as body temperature decreases.^219,282 Atrial dysrhythmias that occur in the absence of underlying heart disease invariably disappear solely with rewarming.

Management

After blood specimens are drawn, the hypothermic patient in whom hypoglycemia is present should be given 0.5 to 1.0 g of dextrose/kg of body weight as D₅₀W (50% dextrose in water in adults or D₂₀W or D₁₀W as appropriate for children) and 100 mg of IV thiamine. If hypoglycemia is the cause of the hypothermia, the response to dextrose may be dramatic, heralded by the onset of shivering and rapid return to normal body temperature. Wernicke encephalopathy is uncommon but may be associated with mild hypothermia; thermoregulation and normal ocular motion may return after the initiation of thiamine therapy.¹⁶¹

Hypothermia shifts the oxygen dissociation curve to the left (Chap. 29), resulting in decreased oxygen unloading to tissues; therefore, oxygen administration may be of benefit.⁶⁷ If clinically indicated, endotracheal intubation should be performed for airway protection or inadequate ventilation or oxygenation.^62,168,198 However, there are case reports of ventricular fibrillation occurring during endotracheal intubation.^{15,100,122,223,291} Every effort should be made to limit patient activity and stimulation during the acute rewarming period because activity may increase myocardial oxygen demand or alter myocardial temperature gradients, increasing the risk of iatrogenic ventricular fibrillation. Although pulmonary artery catheters and central venous lines have been inserted without complications, they should be avoided unless absolutely essential so as not to precipitate ventricular dysrhythmias.^120,169,274 If a central venous catheter is considered necessary, it should not be allowed to touch the endocardium.²⁷⁶ Patients who develop ventricular fibrillation or asystole are difficult to manage because of the many supportive therapies required at once and the often lengthy resuscitation efforts. In these instances, CPR should be initiated and the patient intubated and ventilated to maintain a pH of 7.40, uncorrected for temperature. Active internal rewarming (see later discussion) should be instituted in the patient in cardiac arrest because standard therapy for ventricular fibrillation or asystole may be unsuccessful until rewarming is achieved. There is a risk of toxicity if multiple doses of drugs are administered in the hypothermic patient in whom drug metabolism is altered and circulation is arrested. However, based on current research discussed later, it is reasonable to incorporate pharmacotherapy into the management of hypothermic cardiac arrest. A vasopressor, either epinephrine or vasopressin, may be given to increase the coronary perfusion pressure.²⁹² Amiodarone or lidocaine may then be administered if ventricular fibrillation is present. Defibrillation may not be successful until the temperature exceeds 86°F (30°C); however, defibrillation can be successfully accomplished in animals and patients with temperatures of less than 86°F (30°C).^5,15,63,292 A reasonable approach is that if defibrillation is unsuccessful, defibrillation should not be attempted again until the patient has been warmed several degrees centigrade. Individuals presenting with cardiac arrest and hypothermia may appear dead yet respond to rewarming and resuscitative efforts. Pneumatically powered devices capable of mechanical chest compression and cardiopulmonary bypass are used successfully during prolonged hypothermic cardiopulmonary arrests.^{15,55,172,263,274}

Arterial Blood Gas Physiochemistry in Hypothermia

Assessment of the adequacy of ventilation and oxygenation in the hypothermic patient often poses a dilemma to clinicians because the chemical effects of cold on arterial pH and blood gases lead to confusion in the interpretation of arterial blood gas values. Cold inhibits the dissociation of water molecules, causing pH to increase as cooling occurs. In vitro, the pH change of blood as it is cooled increases parallel to the pH change of neutral water. The partial pressures of CO₂ and O₂ decrease as cooling occurs even as the blood content of those gases remains unchanged. Blood in a syringe taken from a patient whose body temperature is 98.6°F (37°C) yields a pH of 7.40 and a PCO₂ of 40 mm Hg in the blood gas machine at 98.6°F (37°C) but yields a pH of 7.72 and a PCO₂ of 14 mm Hg if the blood is cooled to 61°F (16°C) and the values are measured at that temperature. Specially calibrated laboratory equipment, not routinely available, is required to measure blood gas values directly at other than normal body temperature. A patient whose body temperature is 61°F (16°C) and whose actual in vivo blood gas values are a pH of 7.72 and PCO₂ of 14 mm Hg will have a pH of 7.40 and PCO₂ of 40 mm Hg when the blood is warmed to 98.6°F (37°C) and measured in the standard laboratory blood gas machine. Because the machine measures pH and blood gas pressures only in blood warmed to 98.6°F (37°C) (the uncorrected values), the actual in vivo values in hypothermic patients can be approximated using mathematically derived corrected values. Because the pH of neutrality has also increased, it is unclear what clinical meanings these corrected values have. The uncorrected values indicate what the pH and PCO₂ would be if the patient were normothermic. At first glance, the clinician might be content to learn that a hypothermic patient at 61°F (16°C) has a corrected pH of 7.47 and PCO₂ of 40 mm Hg. However, the uncorrected values in the blood gas machine at 98.6°F (37°C) of pH of 7.18 and PCO₂ of 111 mm Hg indicate that the patient has a significant respiratory acidosis. Attempts to maintain a corrected pH of 7.40 may lead to hypoventilation and risk alveolar collapse and impairment of oxygenation. The preponderance of evidence in the anesthesia and cardiovascular surgery literature suggests that maintenance of ventilation is associated with a decreased incidence of myocardial injury and a decreased incidence of ventricular fibrillation.⁶⁷ Thus, the pH and PCO₂ blood gas values should be left uncorrected after the blood sample is warmed in the blood gas machine and interpreted in the same way as in a normothermic patient.⁶⁷

Hypotension

When hypotension occurs in a patient with hypothermia, it may be a result of the presence of bradycardia and volume depletion. However, hypotension may be a predictor of infection, particularly when associated with a slow rewarming rate. Fluid depletion in hypothermia occurs as a result of a variety of mechanisms, including central shunting of blood by vasoconstriction and cold-induced diuresis. Cold diuresis occurs when increases in central blood volume result in inhibition of the release of antidiuretic hormone. Impairment of renal enzyme activity and decreased renal tubular ­reabsorption contribute to the large quantities of dilute urine known as cold diuresis.^{116,121,169,295}0.9% NaCl should be given to expand intravascular volume. Urine output is an important indicator of organ perfusion and the adequacy of intravascular volume in hypothermic patients, although the initial cold diuresis may lead to underestimation of fluid needs.²⁹⁵

Pharmacologic Interventions

The best means to effect resuscitation of a hypothermic victim in ventricular fibrillation is controversial. The most recent recommendations of the American Heart Association (AHA) for the treatment of cardiac arrest when the core body temperature is below 86°F (<30°C) states that the administration of a vasopressor or antidysrhythmic according to standard Advanced Cardiac Life Support algorithm concurrent with rewarming may be reasonable.²⁷⁹ A metaanalysis of animal studies of antidysrhythmic and vasopressor therapy for ventricular fibrillation in the setting of hypothermia found that there was significant improvement in the return of spontaneous circulation (ROSC) in animals that received epinephrine or vasopressin.²⁹² In this report, the authors could not identify a benefit to the use of amiodarone administered without a vasopressor. They postulated that this is most likely due to the improvement in coronary perfusion pressure caused by vasopressors during cardiac arrest.²⁹²

Epinephrine and Vasopressin.

The administration of vasopressin to pigs in hypothermic cardiac arrest increased coronary perfusion pressure and improved defibrillation success.²⁵² In a pig model, when warmed thoracic lavage was used, vasopressin increased coronary perfusion pressure and increased the 1-hour survival.²⁵¹ In this study, the administration of 0.9% NaCl resulted in zero episodes of successful defibrillation, but all eight vasopressin-treated pigs had restoration of spontaneous circulation after electrical defibrillation and improved short-term survival. The whole-body temperature was not increased, but the authors postulated that myocardial warming may have occurred.²⁵¹ In another study in which epinephrine was given to one group of pigs and vasopressin to another, increased coronary perfusion pressure and ROSC resulted in both groups.^165,166 In contrast, body temperature significantly increased during CPR with thoracic lavage, and epinephrine increased coronary perfusion pressure, but no improvement in ROSC occurred.¹⁶⁴ The length of time of cardiac arrest, the doses of drug, and the efforts to rewarm differed in these studies. A 19 year-old patient who had a prolonged hypothermic cardiopulmonary arrest showed no improvement after 2 mg of epinephrine but had immediate restoration of spontaneous circulation after the administration of vasopressin.²⁶⁹ Interactions with epinephrine, vasopressin, and ischemia during CPR are complex and incompletely understood.¹⁶⁷

Amiodarone.

Amiodarone is recommended in the current AHA algorithm for ventricular fibrillation in normothermia. In one study comparing the use of amiodarone, bretylium, and placebo in a hypothermic dog model, amiodarone showed no statistical improvement in causing ROSC. There was no significant difference among the groups; only one of 10 amiodarone-treated dogs demonstrated ROSC versus three of 10 in the placebo group and four of 10 in the bretylium-treated dogs.²⁶⁷ However, in a study in which hypothermic dogs in ventricular fibrillation were treated with epinephrine before administration of 10 mg/kg of amiodarone, there was a significantly higher rate of ROSC.²⁹²

Dopamine.

Dopamine increases cardiac output, mean arterial pressure, heart rate, and stroke volume in dogs cooled to 77°F (25°C) and stabilizes pulmonary arterial wedge pressure.²⁰⁸ In a canine hypothermia model, dopamine infusions provided some protection from ventricular fibrillation. Dopamine lowered the temperature at which ventricular fibrillation occurred and reduced the incidence of ventricular fibrillation, as did infusion of norepinephrine.⁹ The added benefit of dopamine in hypothermia may be a result of its renal and splanchnic vasodilating properties, increasing renal perfusion and supporting urine output.¹⁰⁴ Dopamine increases myocardial oxygen demand and decreases peripheral perfusion, potentially detrimental effects in hypothermic patients.⁹

Rewarming

Three types of rewarming modalities are used in the management of hypothermic patients.^58,79Passive external rewarming involves covering the patient with blankets and protecting the patient from further heat loss. ­Passive external rewarming uses the patient’s own endogenous heat production for rewarming and is most successful in healthy patients with mild to moderate hypothermia whose capacity for endogenous heat production is intact.¹²¹ Passive external rewarming is reported to be successful in hypothermic patients with temperatures as low as 69°F (20.6°C).^272,282,289 Advocates of passive external rewarming argue that it allows vasoconstriction to persist and decreases the afterdrop and shock from vasodilation associated with active skin rewarming.^121,198,272

Active external rewarming involves the external application of heat to the patient. There is disagreement about the possible detrimental effects of active external rewarming. For example, skin warming may lead to a physiologically detrimental suppression of shivering.¹²¹ Acute vasodilation of peripheral vessels could cause hypotension and an increased peripheral demand on the persistently cold myocardium. The return of cold blood from the extremities to the heart is suggested to exacerbate intramyocardial temperature gradients, which could cause ventricular irritability during hypothermia.¹⁸⁶ However, in pigs, blood returning to the heart was found to be warm before warming of central organs occurred.¹⁰⁵

Afterdrop is the continuing decrease in temperature after rewarming begins. There is no evidence that it occurs in humans.²⁶⁸ In one study of 33 patients with core temperature below 82.4°F (< 28°C), no patient experienced afterdrop during peripheral rewarming.²³⁴ There is no evidence of pooling of blood in the periphery nor of increased flow during surface rewarming.^179,247 Flow studies in the hand, arm, calf, and foot demonstrate that afterdrop has already occurred and is completed before any increase in blood flow occurs in the limbs.^179,286 Initial experiments demonstrating afterdrop were done in inanimate objects and reflected continued cooling of central structures before heat from external sources reached the core.^105,179,286

Mortality rates for active external rewarming are frequently reported to be higher than for passive external rewarming,²²⁹ but case selection is not controlled in these series. Sicker patients with stable cardiac rhythms who fail to rewarm passively and are then actively rewarmed have a higher mortality rate directly correlated with their underlying disease rather than by the method of therapy.⁶⁸ Selection of either passive or active external rewarming in treatment of mild to moderate hypothermic patients with perfusing cardiac rhythms does not appear to influence the prognosis as much as the presence or absence of underlying disease.^{68,134,198,288} In our experience, active external rewarming has not resulted in death except in patients with severe underlying disease.⁶⁸

Active internal rewarming involves attempts to increase central core ­temperature directly by warming the heart before the extremities or ­periphery. Minimally invasive modalities of active internal rewarming include the administration of heated, humidified oxygen delivered by face mask or endotracheal tube¹²³ and gastric lavage with warmed fluids. More invasive modalities, procedures that are fundamental to the rewarming controversy, include peritoneal lavage with warmed dialysate^140,213 and the rerouting of blood through external blood rewarming equipment via cardiopulmonary or femoral–femoral bypass and hemodialysis.^42,128,204 Heparin-coated bypass systems are available that avoid systemic anticoagulation, thus decreasing the risk of bleeding complications. It is suggested that extracorporeal venovenous rewarming and continuous arteriovenous rewarming show improved rewarming rates compared with standard techniques such as saline lavage of the bladder, stomach, or peritoneal cavity.⁹⁸ Extracorporeal methods of active internal rewarming should be reserved for severely hypothermic patients (<80°F or <27°C) or those with unstable cardiac rhythms (ventricular fibrillation, ventricular tachycardia, or asystole) attributed to hypothermia.^5,66,117 In patients with stable rhythms, studies are essential to resolve the debate over the merits of passive or active external rewarming versus active internal rewarming. Transcutaneous pacing was successful in improving hemodynamic parameters and speeding rewarming in an animal model.⁷⁵

Many patients with temperatures below 86°F (30°C) have been successfully treated with passive external rewarming with, at most, the addition of warm, humidified oxygen.^68,259,289 Patient temperature correlates poorly with outcome.^{5,63,168,274,277} Treatment recommendations should not be based solely on temperature. Stability of the vital signs and cardiac rhythm and the underlying cause of hypothermia are much more critical considerations in management.

Hyperkalemia is not described as a consequence of rewarming.⁶² In all of the evidence collected with regard to hyperkalemia, this abnormality was present as a consequence of the hypothermia and not the rewarming.^122,183,248

Prognosis in Hypothermia

Except in cases of profound hypothermia,¹²² the prognosis is most closely correlated with the presence or absence of underlying disease.^{134,198,216,288,289} In patients with hypothermia alone, in the absence of underlying disease, the mortality rate is 0% to 10%. In the presence of a severe underlying disease such as sepsis, the mortality rate is much greater.⁶⁸ Morbidity results from associated frostbite and trauma.

Prolonged cardiopulmonary arrest and absolute temperature are not predictive of poor outcome.^{5,63,168,274,277} In severely hypothermic patients, profound hyperkalemia (K⁺>10 mEq/L) is associated with unsuccessful resuscitation.^122,183,248

Frostbite.

Hypothermia may be accompanied by frostbite when patients are exposed to environmental temperatures that are lower than 20°F (6.7°C).¹⁹⁹ Frostbite should be managed by rapid rewarming of the frozen part of the affected person. The extremity involved may be placed in a large, soft basin of warm water (100–108°F; 38–43°C) for 30 minutes. The water temperature must be frequently adjusted because the frozen extremity will cool the water in the basin. Parenteral analgesics may be necessary because the rewarming ­process is often painful. Frostbitten areas should never be rubbed because the tissue is particularly sensitive to trauma.

Definition of Heatstroke

Heatstroke is defined by a rectal temperature greater than 106°F (41.1°C) in the setting of a neurologic disturbance manifested by mental status changes, including confusion, delirium, stupor, coma, or convulsions.¹⁵⁶ Temperature criteria cannot be absolute because information regarding the patient’s temperature is rarely available at the time of onset of heatstroke. In some instances, the temperature may not be measured for several hours, during which time cooling may have been instituted or occurred spontaneously.^150,151 When appropriate environmental conditions prevail, the diagnosis of heatstroke should be made liberally. Although the absence of sweating was once thought to be an essential component of the definition of heatstroke,^53,214 many patients with heatstroke maintain the ability to sweat.^{61,184,256,283}

Epidemiology of Heatstroke

Hundreds of people die annually of heatstroke in the United States, 80% of whom are older than age 50 years. When counting heat-related fatalities, the number is underestimated if only death certificates are included in which hyperthermia is listed as the underlying cause of death. Including hyperthermia as a contributing factor to death increased the total number of heat-related deaths by 54% from 1993 to 2003.⁴⁴ Several studies show mortality rates from heatstroke to be 5.6% to 80%. Thousands of other ­victims survive with significant heat-related morbidity.^8,260 The high morbidity and mortality of heatstroke markedly contrast with those of profound hypothermia, in which the prognosis is related not to the temperature itself but to the underlying etiology. The overall prognosis in heatstroke depends primarily on how long the temperature has been elevated before cooling, the maximum temperature reached, and the affected individual’s premorbid health.

Heat-related deaths are preventable, and the public health preparedness of cities, health care workers, and the community is essential.^16,45 The mortality rate during heat waves are increased in urban areas where a heat wave has not occurred for several years.^{52,77,141,250} The mortality rate is decreased when public health interventions improve preparedness. The city of Milwaukee experienced a heat wave in 1995 that resulted in numerous public health and preparedness responses. These efforts may have resulted in a diminution by 49% of the number of heat-related deaths and emergency medical service runs in the heat wave of 1999.²⁸⁷ After the Chicago heat wave of 1995, public policies targeting the elderly adults of Chicago may have contributed to a change in the demographics of those who succumbed during a subsequent heat wave in Chicago in 1999. The dead in 1999 were younger; more than 50% of those who died were younger than age 65 years. More than half of the dead were seen or spoken to on either the day of or the day before their death. Psychiatric illness was almost twice as common in the younger victims compared with those older than 65 years of age.²⁰⁷

Heat waves are meteorological events characterized by air temperatures that are 90°F or above (≥32.2°C) for 3 or more consecutive days.⁴⁴ During the summer of 2003, Europe experienced record high temperatures for many consecutive days. The prolonged heat caused extreme increases in mortality rates across Europe. In France, there were 14,800 excess deaths caused by heat. This is equivalent to a total mortality rate increase of 60% between August 1 and August 20, 2003.^170,280 In a follow-up report of 83 of these victims, the mortality rate at 2 years was 71%.¹⁰ Survivors had dramatic decreases in their ability to function.¹⁰ From June to August 2003, Italy reported 1094 excess deaths, a 23% increase compared with the average annual number of deaths from 1995 to 2002.⁴⁵ An increased mortality rate was associated with risk factors previously reported, including old age, limited access to care, poor living conditions, and social isolation.²⁵³

Socially isolated individuals, people with preexisting illnesses, physically compromised individuals, and frail elderly adults are at greatest risk of death during heat waves. Confinement to bed was the strongest predictor of death in the Chicago heat wave of 1995, and living alone doubled the risk of death. There were fewer deaths among people with working air conditioners or who had access to an air-conditioned environment.^235,253 Although fans may seem to improve comfort, they do not prevent heat-related illness and may contribute to heat stress when temperatures and humidity exceed approximately 100°F (37.8°C).^{148,152,153,207,253,294} Prisoners incarcerated in hot conditions die of heatstroke.³⁸ In times of heat waves, preventive public health programs should encourage visiting nurses, housekeepers, and community service programs to increase the awareness of the danger of heat and identify individuals most at risk.²⁵³ A decreased risk of death was found among people with contacts from these agencies during the Chicago heat wave.²⁵³ The media must alert the public and provide information on avoiding heat illness, as well as encourage individuals to help others to stay cool by ensuring access to cooling measures.

The number of deaths from exposure-related illness has increased threefold in foreign transients attempting to enter the United States from Mexico. Because urban areas are more tightly patrolled, individuals attempting to cross into the United States illegally have turned to the harsh deserts and mountain ranges of the southwestern United States, increasing prolonged exposure and resulting in death from heat, cold, and dehydration. Although many more bodies remain undiscovered, 99 individuals’ deaths were attributed to environmental causes in the year 2000, many of them caused by heat.⁸²

From 1995 to 2002, 233 children died from heatstroke when left unattended in cars, 75% of whom were either forgotten or left by caretakers who did not expect the temperature to rise dangerously within the automobile. In 25% of the incidents, children were trapped inadvertently while playing. Most of these deaths occurred during the summer months.¹¹¹

Infants may suffer heatstroke under environmental conditions that would not be expected to place a child in danger. Well-meaning parents sometimes overinsulate children with clothing and blankets, inhibiting their cutaneous heat loss and placing them at risk.^14,137,138

During 2002, the US military reported 1816 heat-related injuries of active duty soldiers.⁶ During Operation Iraqi Freedom, six ­soldiers died from heat-related causes. There were 30 other cases of heatstroke and many other heat-related casualties. During the period from 1997 to 2002, 8084 soldiers were treated as outpatients for heat injuries.⁶ The US military actively promotes heat illness prevention and exhorts its personnel to not repeat history. In comparison, in 1917, 425 British soldiers on active duty in the area on the Persian Gulf (formerly known as Mesopotamia; presently known as Iraq) died of heatstroke during 1 month, and 524 died in 1 year.²⁹¹

There were 114 heatstroke deaths among football players from 1960 to 2007. From 1995 to 2007, 33 football players died of heatstroke—25 high school, five college, two professional, and one sandlot.²⁷⁸

High ambient temperature is associated with an increase in mortality from cocaine overdose. The mean daily number of deaths from cocaine overdose was 33% higher when the ambient temperature exceeded 88°F (31°C).¹⁸⁶

Thermoregulation and Heat Stress

The normal thermoregulatory response to heat stress is mediated primarily by heat-sensitive neurons in the hypothalamus. Increased body core temperature results in active dilation of cutaneous vessels, and skin blood flow increases.^126,238 Because increased skin blood flow is attained primarily by an increase in heart rate and stroke volume, the capacity to increase ­cardiac output is critical to cooling. Compensatory shifting of blood flow from the splanchnic and renal vessels to the skin further increases skin blood flow.^133,238 The combination of vasodilation, increased skin blood flow, and increased sweating results in heat loss through convection and evaporation. Dehydration after profuse sweating increases plasma osmolarity. Heat-sensitive neurons in the preoptic anterior hypothalamus are inhibited by locally increased osmolarity and by input from distal hepatoportal osmoreceptors. The inhibition of heat sensitive neurons results in decreased heat dissipation response.^51,217

Types of Heatstroke

Heatstroke is commonly divided into two types, exertional and nonexertional. Nonexertional, or classic, heatstroke describes heatstroke occurring in the absence of extreme exertion. Nonexertional heatstroke is most commonly described during heat waves, and the victims are predominantly those persons least able to tolerate heat: infants,¹⁴ older adults,⁵⁷ individuals with psychiatric disorders, and chronically ill individuals.

Exertional heatstroke occurs as a result of increased motor activity. It may occur in young, healthy individuals who are exercising or in individuals whose increased motor activity results from other causes, such as seizures or agitation. Often a period of significant heat stress in exercising individuals precedes the development of heatstroke. Military recruits who develop heatstroke may sometimes present to the camp infirmary with vague complaints before collapse.²⁵⁶ Published studies of heatstroke in miners, athletes, and military recruits describe several precipitating factors in heatstroke, including fatigue associated with a recent deficit in sleep, poor physical conditioning, a recent febrile illness, recent heat-related symptoms such as thirst or weakness, relative volume depletion, failure to allow for acclimatization, and obesity. Symptoms of nausea, weakness, headache, diarrhea, or irritability often precede the development of heatstroke. Although rapid onset of symptoms and acute loss of consciousness are frequently reported in exertional heatstroke, the preceding period of heat stress and insidious symptoms may go unrecognized. Although exertional heatstroke is more likely to occur during intense exertion in a hot, humid environment, it may also occur with moderately intense exercise early in the morning, when environmental conditions do not usually represent a thermoregulatory stress.¹²

Differential Diagnosis of Hyperthermia

In addition to exposure and exertion, conditions that predispose to severe hyperthermia include primary hypothalamic lesions, intracranial hemorrhage, agitation, alcohol and sedative–hypnotic withdrawal, seizures, and the use of therapeutic and illicit xenobiotics (Table 30–5).^{102,107,108, and 109,165,187,270} The differential diagnosis may include serotonin toxicity, malignant hyperthermia, or the neuroleptic malignant syndrome, conditions causing high temperature, altered mental status, and increased muscle tone. These conditions are much less common than classical or exertional heatstroke resulting from impaired thermoregulation caused by the effects of therapeutic xenobiotics.

Serotonin Toxicity.

Serotonin toxicity, results from excess stimulation of the serotonin receptors, primarily the 5-HT_1A subtype.²⁶⁶ Drug interactions are most commonly the cause. Monoamine oxidase inhibitors used in conjunction with tricyclic antidepressants,¹⁶ selective serotonin reuptake inhibitors,⁸⁵l-tryptophan,^85,271 meperidine,¹¹⁸ dextromethorphan,²³³ and amphetamines,¹⁶⁵ are reported to lead to serotonergic hyperstimulation and severe symptoms.^103,266 The clinical condition resulting from excess serotonin includes alterations in consciousness, restlessness, increased muscle tone, tremor, GI disturbances, and hyperthermia. Treatment focuses on control of hyperthermia by using aggressive cooling; muscle relaxation ­primarily by using benzodiazepines; or, in severe cases, endotracheal intubation and paralysis (Chap. 75).

Malignant Hyperthermia.

Malignant hyperthermia is a very rare disorder, that is associated with a congenital disturbance of calcium regulation in striated muscle. Malignant hyperthermia was first reported in 1960. Ten deaths occurred in a single family after general anesthesia.⁷² Exposure to anesthetics; depolarizing muscle relaxants; or, rarely, severe exertion precipitates uncontrolled calcium efflux from the sarcoplasmic reticulum, leading to severe muscle rigidity and hyperthermia.^110,139 The clinical setting of severe muscle rigidity and hyperthermia after general anesthesia usually is adequate to define the syndrome (Chap. 69). In other words, malignant hyperthermia is a pharmacogenetic disorder of the ryanodine receptor causing increased sensitivity to certain xenobiotics.^119,246

Neuroleptic Malignant Syndrome.

Neuroleptic malignant syndrome, a severe extrapyramidal syndrome associated with muscle rigidity, autonomic dysfunction, and altered mental status, was first described in 1968.⁶⁹ This disorder develops during the administration of antipsychotics or the withdrawal of dopaminergic xenobiotics. Increased muscle tone because of dopaminergic blockade of the striatum as well as central altered hypothalamic thermoregulation leads to hyperthermia.¹²⁴ Temperature elevation and alteration of mental status occur after the onset of “lead pipe” muscle rigidity.^21,114 Laboratory findings are not specific and include a marked elevation of creatine phosphokinase (CPK) in some patients and leukocytosis with a left shift. Neuroleptic malignant syndrome must be distinguished from the much more common cases of heatstroke in psychiatric patients that are caused by heat intolerance resulting from the anticholinergic effects of antipsychotics or antihistamines prescribed to control extrapyramidal symptoms (Chap. 70).^243,297

Inflammatory Mediators in Heatstroke

The response to heat stress is a coordinated interplay between the mediators of inflammation, including endothelial cells, leukocytes, inflammatory cytokines, and endotoxins. These are important mediators of the systemic immune response. However, in heatstroke, they are responsible for systemic inflammation and activation of the coagulation cascade, similar to the systemic inflammatory response syndrome (SIRS). Many proinflammatory cytokines are identified in heatstroke, including tumor necrosis factor (TNF); interleukins-2, -6, -8, -10, and -12; interferon-α and -β; and granulocyte colony-stimulating factors.²⁸ In one study of 18 heatstroke patients, circulating cytokine concentrations correlated with clinical indices of heatstroke severity.¹³⁵ Cooling delays the release of interleukin-1β, interleukin-6, and TNF in vitro.¹⁵⁵ Studies in hyperthermic animals focus on the modulation of the mediators of inflammation as possible future adjuncts to cooling. In another study, recombinant human activated protein C provided cytoprotection by decreasing release of inflammatory cytokines but did not improve survival.²⁹ Whole-body cooling restored appropriate concentrations of cardiac tissue protein associated with loss of structural integrity of the cardiac myocytes and reversed cardiac dysfunction.⁴⁸

Heat stress causes increased gene transcription of heat shock proteins, which render the organism more resistant to heat injury, protecting cells from injury and increasing cell survival. Heat shock protein 72 is protective against injury and from heat stress, and the extent of protection correlates with the concentration of heat shock protein.¹⁸⁰

During exercise, splanchnic hypoperfusion increases the translocation of bacteria from the gut into the bloodstream, establishing the cascade of inflammation and injury that perpetuates tissue injury after normothermia is established.⁸³

Pathophysiologic Characteristics of Heatstroke

In heatstroke, hypotension and tachycardia are caused by a number of ­factors. The patient with heatstroke may have a reduced plasma volume ­secondary to salt and water depletion. Peripheral pooling of blood is associated with an increase in cutaneous blood flow from 0.5 L/min to 7 to 8 L/min.^133,238 In addition, patients may manifest primary myocardial insufficiency.¹⁵⁷­Clinically, patients exhibit either a hypo- or hyperdynamic circulatory response. The observed circulatory response to heat stress is a function of the patient’s cardiac reserve, volume status, and degree of myocardial heat injury. The hyperdynamic condition is characterized by increased cardiac index and decreased systemic vascular resistance.²¹⁵ These hemodynamic characteristics occur in patients who are able to maintain a significantly increased ­cardiac output in response to the circulatory demand of heat stress.

Volume-depleted patients and those patients with primary myocardial insufficiency may exhibit a hypodynamic response. These patients have a decreased cardiac index and increased systemic vascular resistance.^215,265 Whether pulmonary vascular resistance is affected is unclear. High central venous pressures (CVPs) have been found in some patients, with evidence of right heart failure and right heart dilation on autopsy.¹⁸⁴ These findings have led to the suggestion that pulmonary vascular resistance may be elevated.²¹⁵ In 22 of 34 patients with heatstroke, CVPs were greater than 3 cm H₂O. Twelve patients had a CVP of 0 cm H₂O, and 10 had a CVP that exceeded 10 cm H₂O. These authors cautioned against injudicious infusion of large quantities of IV fluids that can result in complications of congestive heart failure and fluid overload. In the study, only three patients required more than 2 L of 0.9% sodium chloride solution during cooling. Crystalloid infusion ranged from 500 to 2500 mL, and none of the patients developed problems associated with fluid overload.²⁵⁴

A study of compromised elderly patients with heatstroke using pulmonary artery catheters showed that pulmonary vascular resistance was low or normal. Pulmonary capillary wedge pressures were not elevated.²⁶⁴ A study of 13 cases of heatstroke in pilgrims to Mecca, Saudi Arabia, monitored with pulmonary artery catheters demonstrated a good correlation of CVP with pulmonary capillary wedge pressures.² Serial ECGs in 51 of these pilgrims with heatstroke showed normal sinus rhythm in 25%, sinus tachycardia in 52%, atrial fibrillation in 16%, and sinus bradycardia in 6%. ST segment depression and other ST-T wave changes were reported. The QT interval showed no abnormality.³ ST changes suggestive of acute coronary syndrome may occur and normal coronary arteries are noted on coronary catheterization.²⁰² In some patients, echocardiography showed pericardial effusions and regional wall motion abnormalities, asymmetric septal hypertrophy, right ventricular dilation, and left ventricular dilation with impaired function.³

Autopsy studies of the heart demonstrate right heart dilation, pericardial effusions, interstitial edema, degeneration and necrosis of myocardial fibers, and subendocardial hemorrhages.^151,184 Postmortem examination of the lungs revealed vascular congestion, pleural effusions, and parenchymal hemorrhages.^184,215

Gastrointestinal hemorrhage, vomiting, and diarrhea occur ­frequently.²⁵⁶ At autopsy, edema and hemorrhage of the bowel wall occur.⁴⁷ These changes may be partly a result of the regional ischemia of splanchnic blood vessels and resultant hypoperfusion and hypoxia. Increased bowel wall edema and bleeding predispose to the release of bacteria into the bloodstream from the gut, causing focal microvascular changes in the intestinal villi, leading to bowel wall anoxia and further injury.⁸⁶ Liver injury occurs commonly and is not clinically manifest until the second or third day after the temperature increase.^150,256 Centrilobular changes, such as widening of central veins and adjacent sinusoids and pooling of blood, and varying degrees of hepatocellular degeneration are demonstrated on liver biopsy. Repeat biopsies demonstrated that these changes resolve as the patient recovers.¹⁵⁰ In other cases, only congestion and fatty infiltration are reported.⁴⁷

Neuropsychiatric impairment is, by definition, present in all cases of heatstroke, the duration of altered consciousness correlates significantly with mortality.^13,256 Autopsy studies demonstrate a variety of structural and microscopic CNS injuries. Edema and venous congestion are evident. The number of cortical neurons is reduced, with concomitant glial proliferation. Cerebellar Purkinje cell deterioration is marked. The hypothalamus appears to be relatively spared, with limited edema of the neuronal nuclei. Hemorrhages occur throughout the brain.^47,184,256 Carotid artery vasoconstriction occurs in response to heating in an in vitro model using the carotid arteries of rabbits to elucidate the mechanism of ischemia and injury in heatstroke.²⁰⁵ Heatstroke-induced cerebral ischemia is associated with increased glutamate release, activation of cerebral dopaminergic neurons causing dopamine overload, and gliosis. These changes are attenuated by induction of hypothermia in an animal model.⁵⁰

Reports of magnetic resonance imaging (MRI) of brains of patients recovering from heatstroke describe radiographic findings, including hemorrhagic and ischemic abnormalities of the cerebrum and cerebellum, delayed cerebellar atrophy, central pontine myelinolysis, vascular infarcts, and medial thalamic lesions, which correspond anatomically to the paraventricular nucleus.^20,191,192 The paraventricular nucleus is involved with core temperature regulation via the hypothalamic–pituitary–adrenal axis.¹⁹ The clinical symptoms of dysphagia, quadriparesis, wasting extrapyramidal syndrome, and pancerebellar syndrome have corresponding MRI ­findings.⁴ Persistent cerebellar dysfunction occurs, as does lower motor neuron damage, manifested by areflexia and muscle wasting.^70,171 Abnormal nerve conduction studies are documented.¹⁴⁴ Higher cortical functions may be spared in survivors or may be reversible when they occur.^83,174,194 Permanent neurologic sequelae are correlated with the degree and duration of hyperthermia.

Acute kidney injury (AKI) was a major cause of death in heatstroke victims before the advent of hemodialysis.^249,283 In addition to the direct effects of heat, volume depletion, and hypotension, myoglobinuria secondary to rhabdomyolysis results in further renal tubular injury. This is especially common in an agitated or exercising patient.^54,102,224 The mechanism by which myoglobin contributes to AKI remains controversial. At autopsy, the kidneys are enlarged, with extensive petechial hemorrhage.¹⁸⁴ Acute tubular necrosis is demonstrated on biopsy. In exertional heatstroke with AKI, renal hemodynamics are compromised because of increased vasoconstrictive hormones, such as catecholamines, renin, aldosterone, and endothelin-1, and decreased vasodilatory hormones, such as ­prostaglandin E₂.¹⁷⁶

Bleeding is associated with significant morbidity and mortality in many cases of heatstroke. The etiology of coagulation disturbances in patients with heatstroke appear to be multifactorial. Elevation of the prothrombin time may occur within 30 minutes of temperature elevation and is attributed to direct heat injury of clotting factors.¹⁶ Liver damage may significantly contribute to the coagulation disturbances, although this does not manifest as rapidly.^16,206,227 Two patients with severe liver failure secondary to heatstroke received liver transplantation; both died after chronic rejection.²⁴⁰ A third patient with extensive liver cell necrosis as a consequence of heatstroke was referred for consideration of liver transplantation but recovered completely with supportive therapy.⁹⁹ Evidence of diffuse capillary basement membrane injury is demonstrable by electron microscopy and is thought to precipitate consumptive coagulopathy in severe cases of heatstroke.^47,261 Thrombocytopenia is very common and occurs within 30 minutes of onset of heatstroke, frequently in the absence of other evidence of disseminated intravascular coagulation. Direct thermal injury leading to decreased platelet survival and megakaryocyte damage may play a role (Table 30–6).^184,206

Clinical Findings in Heatstroke

Clinical evaluation of a hyperthermic patient begins with careful assessment of the vital signs. Vital sign abnormalities commonly include tachycardia with heart rates greater than 130 beats/min, hypotension, and tachypnea with the respiratory rates often above 30 breaths/min. Most importantly, temperature is elevated. After cooling, there is often a secondary rise in temperature that suggests persistent disturbances of thermoregulation.¹⁸⁴

Neurologic examination reveals a delirious, comatose, or seizing patient. Pupils may be normal, fixed and dilated, or pinpoint. Decerebrate or decorticate posturing may be evident. Muscle tone is increased, normal, or flaccid. The skin may be hot and dry or diaphoretic. Nasal and oropharyngeal bleeding may be present as a consequence of the acute coagulopathy. Examination of the lungs is often nonspecific, although heatstroke victims are at risk of acute respiratory distress syndrome (ARDS) as a primary event associated with capillary endothelial damage or after overly aggressive fluid resuscitation. Cardiac auscultation may reveal a flow murmur secondary to high cardiac output or a right ventricular gallop. Neck vein distension indicates increased CVP. Jaundice suggests hepatic injury and occurs on the second or third day after the onset of heatstroke.⁴⁹ Nasogastric aspiration or rectal examination may demonstrate gross bleeding. A petechial rash develops, probably secondary to capillary endothelial damage.

Laboratory Findings of Heatstroke

Lactate dehydrogenase (LDH) rises as a consequence of diffuse tissue injury. Early rises in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which peak at 48 hours, are indicators of the liver damage that occurs during heatstroke.¹⁵⁰ Muscle enzymes were elevated in all patients in a study of exertional heatstroke²⁵⁶ and in 86% of patients in one study of nonexertional heatstroke.¹⁰⁸ Nonspecific ST- and T-wave changes on ECG are common. Myocardial enzyme elevation occurs and correlates with ECG changes.¹⁵¹ Results of lumbar puncture are nonspecific, are often normal, or may demonstrate elevated CSF protein and lymphocytosis.²⁵⁶

Other laboratory parameters are affected by heatstroke. Salt and water depletion leads to hemoconcentration in patients exposed to elevated temperatures for a period of time. Hypokalemia is common, with potassium deficits as great as 500 mEq occurring during the early period of heat exposure. Arterial blood gas analysis may show a respiratory alkalosis secondary to direct stimulation of the respiratory center by heat or a metabolic acidosis with an elevated lactate concentration.^61,265 Metabolic acidosis is the most frequent acid–base disturbance, either alone or part of a mixed picture. The prevalence of metabolic acidosis correlates with the degree of hyperthermia; 95% of patients demonstrated metabolic acidosis when the body temperature exceeded 107.6°F (42°C).²⁸

Hypophosphatemia is common and is attributed to respiratory alkalosis, which causes intracellular shifts of phosphate. However, eight of ten heatstroke patients developed hypophosphatemia, and none was alkalemic.²⁷ The hypophosphatemia in these patients was associated with increased phosphaturia and decreased tubular reabsorption of phosphorus, a finding that reversed after cooling.¹⁵⁸ Renal tubular damage may also lead to phosphate depletion.¹¹² Phosphate and potassium are elevated when significant muscle injury has occurred. Calcium is normal or low, the latter secondary to binding to damaged muscle tissue. Later, hypercalcemia occurs, possibly as a result of release of this bound calcium.^95,178

Significant alterations occur in lymphocyte subsets in heatstroke victims. One study reported an increased ratio of T-suppressor to T-cytotoxic cells, as well as increased natural killer cells. There was a significant decrease in the percentages of T and B cells and T-helper cells. These changes correlate with the degree of hyperthermia.^25,29 Catecholamines are increased in heatstroke¹ and may affect the distribution of the lymphocyte subsets.²⁵ It is possible that the increased susceptibility to infection described in heatstroke and the alterations in lymphocyte populations are related.²⁵

Effects of Xenobiotics in Heatstroke

Xenobiotics predispose the individual to heatstroke by two primary mechanisms: increased production of heat as a result of xenobiotic action and interference with the body’s ability to dissipate heat because of pharmacologic or toxicologic effects on thermoregulatory centers (Table 30–5). Xenobiotic interactions may cause life-threatening increases in temperature, such as the combination of monoamine oxidase inhibitors with meperidine or dextromethorphan resulting in serotonin toxicity. The uncoupling of oxidative phosphorylation by salicylate, pentachlorophenol, or dinitrophenol leads to the release of metabolic energy as heat rather than trapping that energy in the form of high energy phosphate bonds in ATP. Sympathomimetics may increase heat production by increasing physical activity.

During heat stress, vasodilation leads to increased cutaneous blood flow, resulting in an increased cardiac output. Parasympathetic stimulation results in increased sweating. Xenobiotics that impair these physiologic mechanisms for heat dissipation predispose the individual to heatstroke. Xenobiotics with anticholinergic effects, such as antihistamines, cyclic antidepressants, and antipsychotics, interfere with sweating. Heatstroke as a result of oligohidrosis is reported for zonisamide and topiramate.^160,210 The mechanism is postulated to concern the inhibition of carbonic anhydrase, an enzyme associated with eccrine sweat gland function. Sympathomimetics stimulate α-adrenergic receptors, impairing vasodilation. Antihypertensives and antianginals (most notably calcium channel blockers and β-adrenergic antagonists) with negative inotropic and chronotropic effects impair the ability of the heart to meet the output requirements of increased skin blood flow. Diuretic-induced salt and water depletion also limits cardiac output. Antipsychotics cause hypothalamic depression, altering the normal CNS response to heat stress. Finally, xenobiotics such as ethanol, opioids, and sedative–hypnotics impair normal behavioral responses, and heat-related discomfort may go unnoticed.²⁹²

Heatstroke and Subsequent Heat Intolerance

Whether heatstroke victims are subsequently unable to adapt to exercise in a hot environment remains unclear. Is the heatstroke victim genetically predisposed to heat intolerance, or does heatstroke occur as a result of environmental and host factors? Several studies suggest that heatstroke leads to persistent heat intolerance. These studies often use a single heat intolerance test.^{81,255,257,258} A study of 10 previous heatstroke victims showed no difference in acclimatization responses, thermoregulation, whole-body sodium and potassium balance, sweat gland function, and blood values when compared with control participants.¹² The rate of recovery from exertional heatstroke probably differs among individuals. In this study, one of 10 patients was found to have recurrent heat intolerance 12 months after the study.¹² Resolution of heat intolerance was delayed for 5 months in an individual who had experienced heatstroke twice.¹⁴⁹

Treatment of Heatstroke

Management must focus on the early recognition of hyperthermia. Body temperatures above 106°F (>41.1°C) place the patient at great risk for end-organ injury. Rapid cooling is the first priority and is associated with improved outcomes. Cooling that is delayed allowing body temperatures to remain above 102.2°F (38.9°C) for more than 30 minutes is associated with a high morbidity and mortality. In one report of the Chicago heat wave of 1995, only one patient of 58 victims was cooled within 30 minutes, resulting in an in-hospital mortality rate of 21% and an additional 28% mortality rate within 1 year.⁷¹ Cooling by covering in ice water was twice as rapid in lowering the core temperature as was cooling by using an evaporative spray.¹¹ Ice water immersion results in faster cooling compared with all of the evaporative cooling methods in some studies.^60,88,96 A more recent report of endovascular cooling using a heat exchange balloon catheter demonstrated dangerously lengthy cooling times and inadequate cooling measures.¹⁹³

Successful treatment requires adequate preparation. Equipment needed for rapid cooling should always be readily available in the emergency department and includes fans, ice, and tubs for immersion. En route to the hospital, the patient’s clothes should be removed, and the patient should be covered with ice, if available, and water-soaked sheets. Respiration and cardiovascular status should be stabilized and monitored. Oxygen should be administered. The cause of the heatstroke should be determined and appropriate measures initiated immediately. Xenobiotics, such as antihistamines, butyrophenones, and phenothiazines, and physical restraints that interfere with heat dissipation, such as camisoles and strait jackets, should not be used.¹⁰⁹ Light hand and foot restraints should be used to protect the patient from self-harm. If light restraints are used, the patient should be monitored continuously. A patient who is hyperthermic in the setting of ethanol or sedative–hypnotic withdrawal should be treated with a benzodiazepine.¹⁰⁸ The patient should never be confined to a small, unventilated seclusion room. Adequate cooling, hydration, sedation, and electrolytes and substrate repletion should be ensured.¹⁰⁶

In the emergency department, appropriate laboratory studies should be performed and an IV line inserted. Administration of 100 mg of thiamine should be considered. A rectal probe should be placed for continuous temperature monitoring. The patient should be immersed in an ice bath with a fan blowing over the patient if possible. In addition to the ice bath, iced gastric lavage may be effective.

Agitation, seizures, and cardiac dysrhythmias must be managed while cooling is accomplished. Benzodiazepines are the treatment of choice for agitation and seizures. Heatstroke patients may have significant volume needs, depending on the amount of fluid lost before the onset of ­heatstroke. Hypotension should be treated with fluids and cooling. Volume repletion should be monitored carefully by parameters such as blood pressure, pulse, CVP, and urine output. As the temperature returns to normal, the hypotension may resolve if significant volume deficits are not present.^53,157,159 In patients with myoglobinuria, an attempt should be made to increase renal blood flow and urine output. The use of sodium bicarbonate and mannitol in the prevention of acute tubular necrosis in these cases is controversial.^80,95,237

Phenothiazines and butyrophenones should not be used because they may depress an already altered mental status, may produce hepatotoxicity in a compromised liver, lower the seizure threshold,²⁴ cause acute dystonic reactions, exacerbate hypotension, and interfere with thermoregulation and cooling by affecting the hypothalamus. However, although phenothiazines and butyrophenones may theoretically reduce shivering and the possibility of rebound hyperthermia, their onset of action is slow.²¹⁴ When shivering occurs during cooling, we recommend the judicious use of a benzodiazepine. In addition, benzodiazepines treat ethanol and sedative–hypnotic withdrawal and cocaine toxicity, common causes of hyperthermia.

There is no role for antipyretics in the management of heatstroke. Aspirin and acetaminophen lower temperature by reducing the hypothalamic set point, which is only altered in a patient febrile from inflammation or endogenous pyrogens.^72,126 Heatstroke, however, occurs when cooling mechanisms are overwhelmed and the hypothalamic thermoregulatory set point is not disturbed.¹⁷

Dantrolene is the preferred drug in the treatment of malignant hyperthermia (Antidotes in Depth: A21).^139,285 It acts directly on skeletal muscle and either inhibits the release of calcium or increases calcium uptake through the sarcoplasmic reticulum.³² Its usefulness has not been demonstrated in other conditions associated with hyperthermia, and there is no evidence to support its administration for other conditions.⁷ In a prospective, randomized, double-blind, placebo-controlled study of 52 patients with heatstroke, IV dantrolene at 2 mg/kg of body weight did not alter cooling time.²⁶ There was no significant difference in the mean number of hospital days necessitated by heatstroke victims who received dantrolene and cooling versus those who received cooling alone. Dantrolene may influence central dopaminergic metabolism in patients with neuroleptic malignant syndrome by affecting calcium-triggered neurotransmitter release in the CNS; however, further study is required.²¹² Anecdotal reports of the efficacy of dopamine agonists such as bromocriptine and amantadine have appeared in descriptions of neuroleptic malignant syndrome.¹⁹⁰ No drug therapy should delay the institution of aggressive external cooling (Table 30–7).

• Xenobiotics may disturb normal thermoregulation and result in the abnormal conditions of hyperthermia or hypothermia. These disturbances of homeostasis present significant clinical management ­challenges.

• Hypothermia and heatstroke are preventable conditions.

• Immediate and aggressive cooling is imperative in heatstroke. ­Near-normal body temperature should be achieved within 30 minutes from onset of heatstroke.

• Rewarming of the patient with hypothermia and a stable cardiac rhythm can often be successfully accomplished with patience and without extracorporeal methods.

• Climate change causing increasingly hot weather demands municipal preparedness and public education efforts to prevent deaths during hot conditions.

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