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Definition of Heatstroke
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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
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Epidemiology of Heatstroke
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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.
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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Thermoregulation and Heat Stress
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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
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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.
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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
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Differential Diagnosis of Hyperthermia
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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.
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Serotonin toxicity, results from excess stimulation of the serotonin receptors, primarily the 5-HT1A 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).
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Malignant Hyperthermia.
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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
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Neuroleptic Malignant Syndrome.
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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
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Inflammatory Mediators in Heatstroke
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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
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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
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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
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Pathophysiologic Characteristics of Heatstroke
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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.
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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
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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
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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
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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
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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
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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.
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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
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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
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Clinical Findings in Heatstroke
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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
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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.
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Laboratory Findings of Heatstroke
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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
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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
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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
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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
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Effects of Xenobiotics in Heatstroke
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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.
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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
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Heatstroke and Subsequent Heat Intolerance
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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
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Treatment of Heatstroke
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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
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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
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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.
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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
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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.
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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
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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).
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