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According to the Centers for Disease Control and Prevention, from 1999 to 2010, 7415 deaths were attributable to excessive heat exposure or hyperthermia in the United States.
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With an increased occurrence of heat waves, even in temperate areas, the risk of heat-related illness is rapidly increasing.
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After the onset of heat stroke, the systemic inflammatory response is induced and may continue despite adequate control of body temperature. Coagulopathy and progression to multiple-organ failure may ensue.
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Maintaining organ perfusion and rapid cooling are the major initial treatment goals for patients with heat stroke.
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The central nervous system is particularly vulnerable to heat, with the cerebellum being most susceptible. Pyramidal dysfunction, dysphagia, cognitive changes (ranging from impaired judgment to delirium and coma), quadriparesis, extrapyramidal syndrome, and neuropathy have all been described.
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Extraneurologic organ dysfunction, including the heart, lungs, kidneys, liver, and blood, may evolve even after the patient has been cooled.
The interest in heat-related illnesses has grown substantially, largely because of the effects of climate change and an increased frequency of heat waves. , According to the Centers for Disease Control and Prevention, from 1999 to 2010, excessive heat exposure caused 7415 deaths in the United States. , During this period, more people died of heat-related illness than all other natural disasters combined. , Among the pediatric population, neonates and infants are at highest risk, mainly because of poorly developed thermoregulatory mechanisms and complete dependence on caregivers to provide adequate protection from excessive heat. Children with comorbid conditions, such as developmental delay and various chronic diseases, are also at high risk. Adolescents also may be affected by heat-related injury due to sports-related exertion, poor judgment, or intoxication.
Over the past 2 decades, the understanding of the cellular and molecular responses to heat stress has improved dramatically. At its most severe, heat-related injury produces multiorgan dysfunction through a complex interplay between the cytotoxic effect of the heat and inflammatory and coagulation responses of the host. Despite better understanding of heat injury pathophysiology, treatment remains supportive, with emphasis on immediate cooling. Prevention and education are still the best tools available in the hands of healthcare providers to minimize heat-related morbidity and death.
Definitions
Heat-related illnesses are best regarded as a spectrum of disorders that should be seen as a continuum of increasing severity.
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Heat cramps are painful sustained muscle contractions, most often in the legs or abdominal wall, primarily due to inadequate circulation, dehydration, hyponatremia, and muscle fatigue. Heat has not been shown to directly trigger cramping, and body temperature is usually normal.
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Heat exhaustion is a mild-to-moderate illness due to water or salt depletion from excessive sweating resulting from exposure to high environmental heat or strenuous physical exercise. The patient may have headache, intense thirst, muscle weakness, dizziness, fainting, nausea, and visual disturbances. Core temperature may be normal or elevated but is less than 40°C. Postural hypotension may occur.
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Heat stroke is a life-threatening emergency that occurs when the core temperature exceeds 40°C. Physical manifestations essentially always include central nervous system abnormalities, such as delirium, convulsions, or coma. The pathophysiology of heat stroke is driven by the induction of the systemic inflammatory response syndrome (SIRS). Untreated, heat stroke leads to a syndrome of multiorgan dysfunction. Traditionally, heat stroke has been divided into two types.
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Exertional heat stroke develops in the setting of recreational or occupational exercise. It results from heat production by muscular work, which exceeds the body’s ability to dissipate heat.
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Classic (or nonexertional ) heat stroke develops in the setting of high ambient temperature in the absence of exertion. Classic heat stroke can occur at any age but is particularly prevalent in the very young and in the elderly, the latter of whom frequently possess comorbidities—such as poor mobility, hypertension, and congestive heart failure—that may interfere with the dissipation of body heat.
Epidemiology
Excessive heat is a leading contributor to death by natural events in the United States. From 1999 to 2010, an annual average of 674 deaths in the United States was attributable to “excessive heat exposure.” Because death rates from other causes (e.g., cardiovascular and respiratory disease) increase during heat waves, deaths classified as caused by hyperthermia represent only a portion of heat-related death. Persons aged 15 years and younger accounted for 7% of deaths caused by weather conditions. There is a significant increase in heat-related death rate during heat waves (defined as 3 or more consecutive days of air temperature 90°F or greater (≥32.2°C). For example, in 1980, a year with a record heat wave, the death rate was more than three times higher than that for any other year during the 19-year period of 1979 to 1997. Chicago experienced heat waves in 1990 and 1995 in which there were 103 and 485 heat-related deaths, respectively. Data on heat-related death are imprecise because this condition is misdiagnosed or underdiagnosed, its definition varies, and many patients with near-fatal heat stroke who survive the acute hospitalization have a high 1-year death rate. There is a statistically significant correlation between the number of heat-related illness hospitalizations and the average monthly maximum temperature or heat index (a statistic that combines temperature and humidity). In Saudi Arabia, where the temperature is extremely high, the incidence of heat stroke varies seasonally, from 22 to 250 cases per 100,000 population. Heat-related illness is reported from subtropical and cold parts of the world as well. In Taiwan, a subtropical country without any history of heat waves, a cluster of heat stroke cases was reported during periods of sustained hotter-than-average temperatures. In an observational study in which cold and hot areas in Europe were compared, heat-related death occurred in both types of climates but at higher temperatures in the hot regions, suggesting that the former populations had accommodated to their hotter environments over time.
Within the pediatric population, children younger than 2 years are at higher risk, with specific factors such as diarrheal disease, sweat gland dysfunction, child neglect, and underlying chronic or febrile illness contributing. Children left unattended in parked vehicles remain a principal preventable cause, with an average of 38 fatalities per year in the United States. The majority of cases are male children younger than 2 years. One-quarter of the children were playing and gained access to unlocked vehicles, while the remainder were either intentionally left in the vehicle or forgotten by a caregiver. Additionally, student athletes are at risk of death and disability due to heat-related illness during practice or competition. , The frequency of emergency department visits for athletes with heat illness increased by 133% from 1997 to 2006, and the number of deaths from heat stroke doubled. Heat-related injuries among athletes are particularly frequent in American football, especially during preseason training, which typically occurs at the end of the summer. Obesity and sickle-cell trait may place student athletes at particular risk. Sports associations—specifically, the National Athletic Trainers Association and the National Collegiate Athletic Association—have published guidelines to prevent heat-related injuries in high school and college students, including strong recommendations for a minimum 2-week period of heat acclimation at the start of preseason football practice and limitation on the duration of continuous exercise and protective-equipment use. These are not mandatory, however, and their adoption by state athletic associations is variable. , Alcohol and drug abuse—as well as neuroleptic drugs such as phenothiazines, tricyclic antidepressants, lithium, and fluoxetine taken for medical indications, alone or in conjunction with athletics—may all exacerbate heat-related illness in adolescents.
Pathophysiology of heat-related illnesses
Understanding the systemic and cellular pathophysiology of heat-related illnesses involves an appreciation of thermoregulation, physiologic alterations directly related to hyperthermia, acute-phase response, and production of heat shock proteins (HSPs). For normal enzymatic and cellular function, it is essential that body core temperature be maintained within a narrow range of 37°C ± 0.5 to 0.9°C. , The thermoregulation system, controlled by the preoptic area of the anterior hypothalamus, receives input from thermosensitive receptors in the skin and body core, compares the data with a reference level (the set point ), and responds to an elevation of 0.3°C , with activation of heat loss mechanisms. , ,
Heat dissipation occurs by means of four mechanisms: (1) conduction (i.e., the transmission of heat through direct contact with a cooler surface); (2) convection (i.e., the transfer of heat to moving air or liquid); (3) radiation of heat energy via emanation of electromagnetic energy; and (4) evaporation. Once activated by the hypothalamus, the efferent heat response is both autonomic and behavioral. Blood delivery to the body surface is increased by sympathetic discharge, causing cutaneous vasodilation. Blood flow may increase 8- to 16-fold, up to 8 L/min. Thermal sweating, in response to parasympathetic discharge, can produce approximately 1 L/h per square meter of body surface of sweat. Per liter of evaporated sweat, 588 kCal are lost. Secondary to cutaneous vasodilation and sweating, blood is shunted toward the periphery and visceral perfusion is reduced, especially to the liver, kidneys, and intestines. Rising core temperature will also lead to tachycardia independent of fluid loss, a high cardiac output state, and an increase in minute ventilation. Losses of salt and water through sweating may lead to dehydration and salt depletion, resulting in impaired thermoregulation. When ambient temperature equals or exceeds body temperature, conduction, convection, and radiation cease to be effective. A combination of high ambient humidity and temperature creates a particularly dangerous situation, since at humidity of 90% to 95%, evaporation of sweat stops; under these conditions, the body can no longer eliminate heat by any of its normal mechanisms.
Hyperthermia directly induces cellular injury by causing damage to macromolecules, including proteins, membrane lipids, and deoxyribonucleic acid (DNA). The accumulation of damaged macromolecules triggers the cell to transcribe HSPs, a family of molecules that facilitate stabilization and repair of cellular homeostasis in response to a variety of stressors. , The severity of injury is cumulative; thus, exposure to a high temperature for a brief period of time may cause similar injury to an exposure to a lower temperature for a longer period of time. Cell death is mainly due to apoptosis.
Acclimatization
Prolonged exposure to a hot environment results in adaptation and tolerance to higher temperature levels. Acclimatization to heat may take several weeks and involves multiple organs. Sweat glands develop increased capacity to secrete sweat, plasma volume is increased, and the renin-angiotensin-aldosterone axis is activated, leading to improved salt conservation. The adaptability of the cardiovascular system is probably the most important single determinant of a person’s ability to tolerate heat stress. , Acclimatization is thought to be at least partially mediated by induction of HSP 72. Even acclimatized people have definite limitations for heat tolerance. Once driven beyond a critical level, progression to heat stroke and death may result.
Acute-phase response
A variety of cytokines are produced in the acute phase of heat stress. Plasma levels of both proinflammatory cytokines (tumor necrosis factor–α [TNF-α], interleukin [IL]-1, and interferon-γ) and antiinflammatory cytokines (IL-6, IL-10, TNF receptors p55 and p75) are elevated in patients with heat stroke. Soluble TNF, IL-2, and IL-6 receptors are also elevated in heat stroke. , It has been shown that the severity of symptoms during heat stroke correlates with IL-1 and IL-6 levels. The acute-phase response may continue after the patient is cooled. Onset of inflammation may be local, with systemic progression , involving endothelial cell activation, release of endothelial vasoactive factors, and endothelial cell injury. The gastrointestinal tract may also play a role in the exaggeration of the inflammatory response. Vascular congestion, hemorrhage, thrombosis, and massive loss of surface epithelium in the jejunum were observed in a baboon model of heat stroke. These changes facilitate bacterial and endotoxin translocation and release of mitochondrial DNA fragments, which contribute significantly to SIRS and multiple-organ dysfunction syndrome (MODS).
Endothelial cell injury activates both the coagulation and fibrinolytic systems. Microvascular thrombosis is found in many organs of deceased heat stroke patients. Heat stress by itself is a procoagulation condition because it causes platelet clumping in small vessels. Injured endothelium plays an important role in producing and releasing both procoagulant and anticoagulant substances (e.g., von Willebrand factor antigen [vWF-Ag], tissue plasminogen activator, and plasminogen activator inhibitor). , Circulating vWF-Ag, thrombomodulin, endothelin-1, nitric oxide (NO) metabolites, soluble E-selectin, and intercellular adhesion molecule-1 (ICAM-1) are elevated in heat-related illness, creating a clinical picture of disseminated intravascular coagulation (DIC). , Cooling patients with heat stroke reverses only part of these coagulation abnormalities.
In some animal models of heat stroke, inhibiting the inflammatory response by administering corticosteroids, IL-1 receptor antagonist, or recombinant activated protein C prevented organ damage. In contrast, studies using a baboon model of heat stroke demonstrated that corticosteroids given before or at the onset of induced heat stroke exacerbated tissue injury and accelerated progression to MODS. In addition, in mouse studies in which TNF receptor or IL-6 was knocked out, animals with heat stroke had higher mortality. The promotion of endogenous mediators by heat thus appears to be protective in some contexts and harmful in others. More recent studies in rodents suggests that the inflammatory response is mediated by the high-mobility group box 1 (HMGB1) proteins that are released by heat-injured cells. , These molecules act on toll-like receptor 4 and initiate a proinflammatory cascade mediated by nuclear factor-κB (NF-κB). Further characterization of these molecular pathways may help us to better understand the pathophysiologic and adaptive role of the host immune response to heat stress.
Clinical features of heat stroke
Heat exhaustion may produce relatively mild dysfunction of multiple organs, but heat stroke typically is associated with severe MODS. Recognition and support of these multifarious manifestations is critical to a successful outcome.
Central nervous system
Neurologic dysfunction is a cardinal feature of heat stroke. Brain dysfunction is usually severe but may be subtle, manifesting only as inappropriate behavior or impaired judgment. More often, patients present with delirium or coma. Seizures may occur, especially during cooling. The central nervous system is particularly vulnerable to heat, the cerebellum being most susceptible. Proton magnetic resonance imaging is a useful tool for evaluating major metabolic changes in the cerebellum after heat stroke. Pyramidal dysfunction, dysphagia, mental status changes, quadriparesis, extrapyramidal syndrome, and peripheral neuropathy have all been described. , No data regarding long-term neurologic outcome in children have been reported.
Cardiovascular
Cardiovascular dysfunction is common in heat stroke. Hypotension and shock may result from splanchnic vasoconstriction and cutaneous vasodilation aimed to facilitate heat dissipation. Dehydration, combined with redistribution of blood volume, leads to reduction in venous pressure and diastolic filling. , Circulation is hyperdynamic in these patients, with tachycardia and high cardiac output. Vasomotor tone may remain abnormally low, even after normal temperature and intravascular volume have been restored.
Electrocardiographic changes are common in heat stroke but are nonspecific and include QT segment prolongation and ST-T wave changes. Less frequently, the patient may experience multiform premature ventricular contractions, ventricular tachycardia, and other dysrhythmias. The electrocardiographic abnormalities are transient, typically subsiding with cooling and correction of potassium, magnesium, and calcium abnormalities.
Pulmonary
The pulmonary system is not involved in early stages of heat-related illnesses. However, approximately 25% of adults with heat stroke acquire acute respiratory distress syndrome (ARDS). Patients with ARDS have poor prognosis, with up to 75% mortality rate. Lung involvement frequently occurs as part of MODS.
Renal
Elevated blood urea nitrogen and creatinine levels are seen even in mild heat-related disease such as heat cramps. Incidence of acute kidney injury ranges from 5% in classic heat stroke to 25% in exertional heat stroke. Direct thermal injury, hypoperfusion, rhabdomyolysis with myoglobinuria, release of vasoactive mediators, and DIC may all contribute to renal injury. , , ,
Gastrointestinal
Gastrointestinal involvement in heat stroke occurs secondary to splanchnic vasoconstriction and gut hypoperfusion. , , Jejunal injury may lead to diarrhea. The liver may be severely injured in heat stroke. This is a metabolically active organ and a major site of heat production. During periods of hyperthermia, liver temperature is among the highest of any organ in the body, putting it at high risk for injury. Abnormal liver function tests may be seen during heat-related illnesses. Elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GT), lactate dehydrogenase (LDH), and total bilirubin has been described. , , Patients with heat stroke demonstrate a typical rise in AST and ALT levels starting 30 minutes from onset, peaking at 48 to 72 hours following injury, with return to normal values after 10 to 14 days. , Severe liver damage is more common in exertional heat stroke. Fulminant liver failure is rare and usually carries a grave prognosis even with liver transplantation.
Metabolic
Early in the course of heat injury, the most common acid–base abnormality is a mixed non–anion gap metabolic acidosis and respiratory alkalosis. Hypokalemia resulting from respiratory alkalosis, sweat losses, and renal wasting may change to hyperkalemia because of cellular potassium leak. Several hours into the injury, the clinical picture changes into a predominantly metabolic acidosis caused by sustained tissue injury. , , Hyponatremia is the most common sodium abnormality and is typically asymptomatic. Hypernatremia is rare but associated with worse outcome.
Hematologic
Anemia, thrombocytopenia, prolonged clotting time, and DIC are well documented in patients with heat stroke. , , , Worsening coagulopathy may occur a few days after cooling. Rapid drop of hematocrit in the first 24 hours following heat stroke is a common feature. This is partially explained by rehydration but is most probably multifactorial. The red blood cell (RBC) half-life is shortened after heat stroke; RBCs are more fragile following exposure to high temperatures, leading to early removal from the circulation. Hypersegmented neutrophils may be observed in peripheral blood for the first few hours following the onset of heat stroke. The cause for this phenomenon is unclear. These cells are thought to be undergoing changes associated with apoptosis.
Infectious
In the early phase of heat stroke, blood cultures are negative. In one adult study, 27% of patients had positive blood cultures and 25% had positive urine cultures 24 hours after heat stroke. The incidence of bacterial infections in the pediatric population with heat stroke is unknown.
Treatment
Heat exhaustion is usually a benign clinical entity, requiring only removal of the patient from the hot environment, rest, and rehydration. Referral of the more severe cases to medical attention may be necessary for intravenous fluid resuscitation and assessment of end-organ injury. By contrast, heat stroke is a medical emergency, with a successful outcome depending on immediate recognition and intervention. Rapid cooling and maintenance of organ perfusion and function are the major goals of treatment of heat stroke. Treatment should be started promptly at the scene with removing the patient from the circumstances that led to heat stroke in order to prevent further increase in core temperature. Adherence to basic resuscitative guidelines is required, with protection of the airway and management of breathing. After the airway is secured, the child with heat stroke should be moved to a cool environment, clothes should be removed, intravenous access should be obtained, and a normal saline or lactated Ringer’s solution bolus should be administered. Fluid resuscitation, besides ensuring organ perfusion, increases heat dissipation and lowers core temperature by improving skin blood flow.
Cooling should be started as early as possible with readily available methods. Cooling to <39°C within 30 minutes yields survival rates of 90% to 100% in cases of exertional heat stroke and 40% to 85% in classic heat stroke. , The rule of “cool first, transport second” applies. This recommendation does not discount the requirement for advanced critical care at the hospital but rather prioritizes cooling in the first 30 minutes after collapse, which is critical for survival.
Various cooling methods have been used to promote heat loss, but controversy remains regarding the best cooling technique. Some investigators regard ice water immersion to be the most efficient cooling method. Indeed, ice water immersion was twice as rapid in reducing the core temperature as the evaporative spray method in patients with exertional heat stroke and five times faster than simply placing the patient in an air-conditioned room. Rapid cooling is effected through conduction of body heat across a large temperature gradient. Ice water is readily available and does not require special equipment. It is estimated that ice water immersion cools the body at a rate of 0.15 to 0.22°C per minute. Some studies have indicated that cooling by ice water immersion, particularly in exertional heat stroke, is associated with 0% mortality. However, it should be noted that some of these investigations applied the method to athletes and military personnel, populations who are intrinsically physically fit, immediately after onset of symptoms, which may account in part to its reported high success rate. Others claim that there is no evidence to support the superiority of any cooling technique, especially in classic heat stroke. , Critics of immersion point out that it may complicate resuscitation efforts of the comatose child who requires endotracheal intubation, mechanical ventilation, and close observation. These disadvantages may be partially overcome by applying ice packs to the entire body rather than immersion in an ice cold bath, although the ice must cover the entire body; confining the application to the axilla and groin, as recommended by some, produces inferior cooling. Ice application is uncomfortable to the conscious child and may cause shivering and combativeness, but both may be ameliorated with benzodiazepines or narcotics.
Sponging the patient with ice water while massaging the body to promote cutaneous vasodilation as a fan blows air across the patient—thus employing convection and evaporation to lower body temperature—has been demonstrated to be effective, particularly in nonexertional heat stroke. The rapidity of lowering body heat with this technique is variable, however, likely due to differences in the temperature of the water applied to the patient and the strength of the fan. Evaporative/convective cooling has been made more uniform with the use of special cooling units, but the concept of keeping the patient “wet and windy” can be effectively achieved without specialized equipment with the application of tepid water to the skin while a commercial fan is used to keep high air flow across the patient in a cool ambient temperature.
Cooling blankets are widely used in the pediatric ICU (PICU) setting, but while the effectiveness of these devices has been evaluated in patients with fever, no data are available concerning their utility in heat stroke patients. Invasive cooling techniques—including iced peritoneal lavage as well as bladder and gastric lavage—have been suggested. Peritoneal lavage is difficult to perform and requires placement of a peritoneal catheter by trained personnel. Evidence for gastric lavage comes mostly from canine models and was found to have no advantage over evaporative cooling. Recent reports of an intravascular cooling device to control body temperature found the system to be highly effective. However, there are only case reports regarding its use on patients with heat stroke; thus, it cannot be recommended at this point. , Hence, all of these techniques should be considered, at most, adjuvant to the more traditional methods for cooling. Antipyretics are not recommended for treatment of heat stroke. These drugs lower body temperature by normalizing the elevated hypothalamic set point. In heat stroke, the elevated body temperature reflects failure of the cooling mechanism rather than an abnormal set point. Salicylates and acetaminophen should be avoided owing to their potential to aggravate coagulopathy and hepatic injury. , Dantrolene has been used successfully for malignant hyperthermia and neuroleptic malignant syndrome. There are conflicting data regarding its effectiveness in heat stroke.
Once a core body temperature of less than 39°C has been achieved, active cooling may be stopped. This end point appears to be safe in terms of mortality, but it should be noted that a safe end point regarding long-term morbidity, particularly for neurologic outcome, has not yet been established. Induced hypothermia has not been evaluated for effectiveness with heat stroke. A recent study looking at therapeutic hypothermia after out-of-hospital cardiac arrest in children showed no benefits in survival with good neurologic outcome. Hence, it is unlikely to be beneficial in pediatric patients with heat stroke. All pediatric patients with heat stroke should be observed in the PICU, even if respiratory support is not required. Basic laboratory evaluation should include monitoring of electrolytes, renal and liver function tests, complete blood count, creatine kinase, and coagulation studies. Urine output should be followed closely, and a urine sample should be sent for myoglobin analysis.
Prevention is still the best approach to heat-related illness. Whenever possible, people should acclimatize themselves to hot weather. Physical activity should be undertaken during cooler hours, and fluid intake should be increased. Children should never be left unattended in a closed car, especially during hot weather, and guidelines to prevent heat-related injuries in student athletes should be promoted and followed. Physicians’ awareness and knowledge may promote diagnosis of early forms of heat-related illness, thus, preventing progression to heat stroke. On a national level, a good weather forecasting system and air-conditioned shelters for vulnerable populations may decrease heat-related morbidity and death during heat waves. ,
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