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Thermoregulatory disorders and illness related to heat and cold stress

Open AccessPublished:January 06, 2016DOI:https://doi.org/10.1016/j.autneu.2016.01.001

      Highlights

      • Hypothermia (core temperature < 35.0 °C) and hyperthermia (core temperature > 40.5 °C) are medical emergencies.
      • Severely hypothermic patients are at risk of cardiac arrhythmias, including atrial and ventricular fibrillation.
      • The clinical feature that best differentiates heat stroke from heat exhaustion is a change in mental status.
      • Anhidrosis may be present in classical, but usually not in exertional, heat stroke. Sweating does not exclude heat stroke.
      • Ice water immersion for heat stroke should begin as early as possible to lower core temperature within 30 minutes

      Abstract

      Thermoregulation is a vital function of the autonomic nervous system in response to cold and heat stress. Thermoregulatory physiology sustains health by keeping body core temperature within a degree or two of 37 °C, which enables normal cellular function. Heat production and dissipation are dependent on a coordinated set of autonomic responses. The clinical detection of thermoregulatory impairment provides important diagnostic and localizing information in the evaluation of disorders that impair thermoregulatory pathways, including autonomic neuropathies and ganglionopathies. Failure of neural thermoregulatory mechanisms or exposure to extreme or sustained temperatures that overwhelm the body's thermoregulatory capacity can also result in potentially life-threatening departures from normothermia. Hypothermia, defined as a core temperature of <35.0 °C, may present with shivering, respiratory depression, cardiac dysrhythmias, impaired mental function, mydriasis, hypotension, and muscle dysfunction, which can progress to cardiac arrest or coma. Management includes warming measures, hydration, and cardiovascular support. Deaths from hypothermia are twice as frequent as deaths from hyperthermia. Hyperthermia, defined as a core temperature of >40.5 °C, may present with sweating, flushing, tachycardia, fatigue, lightheadedness, headache, and paresthesia, progressing to weakness, muscle cramps, oliguria, nausea, agitation, hypotension, syncope, confusion, delirium, seizures, and coma. Mental status changes and core temperature distinguish potentially fatal heat stroke from heat exhaustion. Management requires the immediate reduction of core temperature. Ice water immersion has been shown to be superior to alternative cooling measures. Avoidance of thermal risk and early recognition of cold or heat stress are the cornerstones of preventive therapy.

      Keywords

      1. Introduction

      Temperature is a critical variable in health and disease. Constraint of human body core temperature within a degree or two of 37 °C, which is the optimal temperature for normal cellular function, occurs in three ways. The first is stable climate, which maintains temperatures across most of the surface of planet Earth within a range compatible with human life. The second is the autonomic nervous system, which reacts robustly to thermal challenges by orchestrating a complex array of neural responses below the level of conscious awareness. The autonomic responses to cold stress include cutaneous vasoconstriction to retain bodily heat as well as metabolic and shivering thermogenesis. The autonomic responses to heat stress include cutaneous vasodilatation, which liberates heat by radiant and convective heat loss, and sweating, which liberates heat by evaporation. The third and perhaps least predictable is human behavior, which responds to thermal sensory input by seeking warmth or coolness, but which also is responsible for getting people into situations of cold or heat stress, some of which can threaten life or health. Another aspect to human behavior is the healthcare professional's response to thermoregulatory disorders, which draws from knowledge of autonomic physiology to treat patients who have been rescued from circumstances that challenge their capacity for thermoregulation.
      This clinical review has a dual emphasis. The first is thermoregulatory disorders, which are disorders of the autonomic nervous system that impair the pathways involved in thermoregulation. Whereas these disorders sometimes present with symptoms related to heat or cold stress, more often the thermoregulatory deficit is incidental to symptoms and provides colocalizing information that is helpful to reaching an accurate diagnosis. The second is illness related to heat stress or cold stress, which encompasses common clinical presentations in which autonomic thermoregulatory function or dysfunction plays a role. Environmental conditions of extreme or prolonged heat or cold stress can overwhelm human thermoregulatory capacity, even in healthy persons, but especially for those whose capacity is impaired. Each year in the United States, for example, approximately 2000 people die from weather-related causes of death (
      • Berko J.
      • Ingram D.D.
      • Saha S.
      • Parker J.D.
      Deaths attributed to heat, cold, and other weather events in the United States, 2006–2010.
      ). The National Center for Health Statistics found that 63% of these were attributed to exposure to excessive or prolonged natural cold, hypothermia, or both; whereas 31% were attributed to exposure to excessive natural heat, heat stroke, or sun stroke. As these statistics were gathered from death certificates, the numbers may underestimate the true incidence of fatal thermoregulatory catastrophe (
      • Berko J.
      • Ingram D.D.
      • Saha S.
      • Parker J.D.
      Deaths attributed to heat, cold, and other weather events in the United States, 2006–2010.
      ).

      2. Measurement of body temperature

      The bodily temperatures most relevant in medicine are those of the internal organs, particularly the brain, heart and liver. The temperature of the vital internal organs is referred to as the core temperature. The clinical importance of the core temperature relates to the fact that the central nervous system, especially the cerebellum, and the liver are especially sensitive to heat stress (
      • Atha W.F.
      Heat-related illness.
      ,
      • Kiyatkin E.A.
      Brain temperature homeostasis: physiological fluctuations and pathological shifts.
      ). Heat-related injury also impacts the kidneys, gastrointestinal tract, and myocardium (
      • Atha W.F.
      Heat-related illness.
      ,
      • Jardine D.S.
      Heat illness and heat stroke.
      ,
      • Wexler R.K.
      Evaluation and treatment of heat-related illnesses.
      ). A number of methods are available in clinical practice, and each has its advantages and disadvantages (Table 1).
      Table 1Comparison of methods for measuring body temperature.
      Site of measurementAdvantagesDisadvantages
      Forehead skinEase of useHighly inaccurate
      AxillaryEase of use

      Inexpensive

      Approximates core temperature in newborns

      If normal, can rule out hypothermia
      Inaccurate in children and adults due to air exposure and sweat
      OralEase of use

      Inexpensive
      Hazards of broken glass and mercury

      Underestimates core temperature due to air or beverage exposure or variable probe placement
      Tympanic membraneEase and speed of use

      More closely estimates core temperature than oral methods

      Reasonably accurate in children and adults
      Accuracy is limited by air or cerumen in ear canal
      Temporal arteryEase of use in children

      Accuracy as compared to other noninvasive methods
      Less accurate in children younger than 5 and febrile adults
      RectalAccurate core temperature at steady state

      Most reliable for assessing exertional heat stroke
      Uncomfortable

      Lags changes in core temperature

      May underestimate hepatic or brain hyperthermia

      Potential for transmission of stool-borne pathogens

      Rarely traumatic injury to rectum
      EsophagusReduced risk of thermal injury to esophagus during left atrial ablation proceduresRequires an invasive esophageal probe
      BladderUseful indicator of core temperature to prevent intraoperative and postoperative hypothermiaRequires insertion of a bladder catheter

      Lags changes in core temperature during cardiopulmonary bypass
      Pulmonary arteryMost accurate core temperatureRequires an invasive pulmonary artery catheter

      2.1 Invasive techniques

      Whereas direct measurement of brain temperature in clinical settings is impractical, the pulmonary artery temperature, as measured by a thermistor in a pulmonary artery catheter, is considered the gold standard for accurate determination of core temperature in clinical settings where invasive measurements are possible (
      • Pearson J.
      • Ganio M.S.
      • Seifert T.
      • et al.
      Pulmonary artery and intestinal temperatures during heat stress and cooling.
      ,
      • Lefrant J.Y.
      • Muller L.
      • de la Coussayre J.E.
      • et al.
      Temperature measurement in intensive care patients: comparison of urinary bladder, oesophageal, rectal, axillary, and inguinal methods versus pulmonary artery core method.
      ). Other internal sites at which core temperature has been measured include the esophagus, intestines, rectum, and bladder (
      • Lefrant J.Y.
      • Muller L.
      • de la Coussayre J.E.
      • et al.
      Temperature measurement in intensive care patients: comparison of urinary bladder, oesophageal, rectal, axillary, and inguinal methods versus pulmonary artery core method.
      ,
      • Robinson J.L.
      • Seal R.F.
      • Spady D.W.
      • Joffres M.R.
      Comparison of esophageal, rectal, axillary, bladder, tympanic, and pulmonary artery temperatures in children.
      ). Monitoring of esophageal temperature during left atrial radiofrequency procedures for atrial fibrillation, for example, has been shown to reduce the risk of thermal injury to the esophagus (
      • Liu E.
      • Shehata M.
      • Liu T.
      • et al.
      Prevention of esophageal thermal injury during radiofrequency ablation for atrial fibrillation.
      ,
      • Leite L.R.
      • Santos S.N.
      • Maia H.
      • et al.
      Luminal esophageal temperature monitoring with a deflectable esophageal temperature probe and intracardiac echocardiography may reduce esophageal injury during atrial fibrillation ablation procedures: results of a pilot study.
      ).
      For the vast majority of patients who do not have indwelling catheters, rectal thermometry has evolved as the standard method for determining core temperature (
      • Lefrant J.Y.
      • Muller L.
      • de la Coussayre J.E.
      • et al.
      Temperature measurement in intensive care patients: comparison of urinary bladder, oesophageal, rectal, axillary, and inguinal methods versus pulmonary artery core method.
      ,
      • Robinson J.L.
      • Seal R.F.
      • Spady D.W.
      • Joffres M.R.
      Comparison of esophageal, rectal, axillary, bladder, tympanic, and pulmonary artery temperatures in children.
      ). Rectal thermometry is not ideal, however, as rectal temperatures may lag changing temperatures in the blood and other deep organs (
      • Robinson J.L.
      • Seal R.F.
      • Spady D.W.
      • Joffres M.R.
      Comparison of esophageal, rectal, axillary, bladder, tympanic, and pulmonary artery temperatures in children.
      ,
      • Eichna L.W.
      • Berger A.R.
      • Rader B.
      • Becker W.H.
      Comparison of intracardiac and intravascular temperatures with rectal temperatures in man.
      ). Rectal thermometry also involves physical and psychological discomfort, and there have been documented cases of nosocomial transmission of stool-borne pathogens (
      • Livornese L.L.J.
      • Dias S.
      • Samuel C.
      • et al.
      Hospital-acquired infection with vancomycin-resistant Enterococcus faecium transmitted by electronic thermometers.
      ,
      • McAllister T.A.
      • Roud J.A.
      • Marshall A.
      • et al.
      Outbreak of Salmonella eimsbuettel in newborn infants spread by rectal thermometers.
      ) and, very rarely, traumatic injury to the rectum (
      • Al-Qahanti A.
      • El-Wassabi A.
      • Al-Bassam A.
      Mercury-in-glass thermometer as a cause of neonatal rectal perforations: a report of three cases and review of the literature.
      ).

      2.2 Noninvasive techniques

      In common clinical practice, noninvasive methods approximate core temperature indirectly. The traditional method of taking oral temperature with a sublingual mercury-in-glass thermometer has, in recent decades, yielded to new technologies that avoid the potential hazards of broken glass and liquid mercury (
      • Zhen C.
      • Xia Z.
      • Long L.
      • Pu Y.
      Accuracy of infrared ear thermometry in children: a meta-analysis and systematic review.
      ,
      • Apa H.
      • Gözmen S.
      • Bayram N.
      • et al.
      Clinical accuracy of tympanic thermometer and noncontact infrared skin thermometer in pediatric practice: an alternative for axillary digital thermometer.
      ,
      • Batra P.
      • Goyal S.
      Comparison of rectal, axillary, tympanic, and temporal artery thermometry in the pediatric emergency room.
      ,
      • El-Radhi A.S.
      • Patel S.
      An evaluation of tympanic thermometry in a paediatric emergency department.
      ,
      • Gasim G.I.
      • Musa I.R.
      • Abdien M.T.
      • Adam I.
      Accuracy of tympanic temperature measurement using an infrared tympanic membrane thermometer.
      ,
      • Jefferies S.
      • Weatherall M.
      • Young P.
      • Beasley R.A.
      A systematic review of the accuracy of peripheral thermometry in estimating core temperatures among febrile critically ill patients.
      ,
      • Penning C.
      • van der Linden J.H.
      • Tibboel D.
      • Evenhuis H.M.
      Is the temporal artery thermometer a reliable instrument for detecting fever in children?.
      ). The most sensitive temperature sensors are thermistors, which are semiconductors, the electrical resistance of which varies in proportion to temperature (
      • Bhavaraju N.C.
      • Cao H.
      • Yuan D.Y.
      • et al.
      Measurement of directional thermal properties of biomaterials.
      ). Other types of contact sensors include thermocouples, which are constructed with a pair of dissimilar metal wires joined at one end, resistance temperature detectors, which are wire windings or film serpentines, and liquid crystal strips. These have in common a temperature-dependent physical property that translates to a measurable change in an electric circuit to which the sensor is connected (
      ). Temperature can also be measured remotely by an infrared sensor pointed at the skin or tympanic membrane surface (
      • Tse J.
      • Rand C.
      • Carroll M.
      • et al.
      Determining peripheral skin temperature: subjective versus objective measurements.
      ).
      Numerous studies have compared the clinical use of rectal, oral, axillary, tympanic membrane, and temporal artery thermometry, with varying and at times conflicting results (
      • Allegaert K.
      • Casteels K.
      • van Gorp I.
      • Bogaert G.
      Tympanic, infrared skin, and temporal artery scan thermometers compared with rectal measurement in children: a real-life assessment.
      ,
      • Bodkin R.P.
      • Acquisto N.M.
      • Zwart J.M.
      • Toussaint S.P.
      Differences in noninvasive thermometer measurements in the adult emergency department.
      ,
      • Charafeddine L.
      • Tamim H.
      • Hassouna H.
      • et al.
      Axillary and rectal thermometry in the newborn: do they agree?.
      ,
      • Odinaka K.K.
      • Edelu B.O.
      • Nwolisa C.E.
      • et al.
      Temporal artery thermometry in children younger than 5 years: a comparison with rectal thermometry.
      ,
      • Zhen C.
      • Xia Z.
      • Long L.
      • Pu Y.
      Accuracy of infrared ear thermometry in children: a meta-analysis and systematic review.
      ,
      • Apa H.
      • Gözmen S.
      • Bayram N.
      • et al.
      Clinical accuracy of tympanic thermometer and noncontact infrared skin thermometer in pediatric practice: an alternative for axillary digital thermometer.
      ,
      • Batra P.
      • Goyal S.
      Comparison of rectal, axillary, tympanic, and temporal artery thermometry in the pediatric emergency room.
      ,
      • Gasim G.I.
      • Musa I.R.
      • Abdien M.T.
      • Adam I.
      Accuracy of tympanic temperature measurement using an infrared tympanic membrane thermometer.
      ,
      • Huggins R.
      • Glaviano N.
      • Negishi N.
      • et al.
      Comparison of rectal and aural core body temperature thermometry in hyperthermic, exercising individuals: a meta-analysis.
      ,
      • Edelu B.O.
      • Ojinnaka N.C.
      • Ikefuna A.N.
      Fever detection in under 5 children in a tertiary health facility using the infrared tympanic thermometer in the oral mode.
      ,
      • Penning C.
      • van der Linden J.H.
      • Tibboel D.
      • Evenhuis H.M.
      Is the temporal artery thermometer a reliable instrument for detecting fever in children?.
      ,
      • Jefferies S.
      • Weatherall M.
      • Young P.
      • Beasley R.A.
      A systematic review of the accuracy of peripheral thermometry in estimating core temperatures among febrile critically ill patients.
      ,
      • El-Radhi A.S.
      • Patel S.
      An evaluation of tympanic thermometry in a paediatric emergency department.
      ,
      • Craig J.V.
      • Lancaster G.A.
      • Taylor S.
      • et al.
      Infrared ear thermometry compared with rectal thermometry in children: a systematic review.
      ,
      • Greenes D.S.
      • Fleisher G.R.
      Accuracy of a noninvasive temporal artery thermometer for use in infants.
      ). Considering these studies as a whole, it may be concluded that the appropriate choice of method depends on the clinical context, as physiologic conditions vary considerably depending on whether the patient is hyperthermic or hypothermic, the external environment, the rate of thermal change, and the age and medical acuity of the patient.
      In the evaluation of hyperthermia, all but rectal temperature have been shown to be inadequate for monitoring individuals exercising outdoors in the heat (
      • Bach A.J.
      • Stewart I.B.
      • Disher A.E.
      • Costello J.T.
      A comparison between conductive and infrared devices for measuring mean skin temperature at rest, during exercise in the heat, and recovery.
      ,
      • Casa D.J.
      • Becker S.M.
      • Ganio M.S.
      • et al.
      Validity of devices that assess body temperature during outdoor exercise in the heat.
      ). Even rectal temperature, however, does not always accurately reflect the temperature in other deep organs, as in nonsteady state conditions rectal temperatures lag changes in core temperature (
      • Giesbrecht G.G.
      Cold stress, near drowning and accidental hypothermia: a review.
      ). In particular, rectal temperature readings may underestimate hepatic temperature and the potential for hepatocellular heat-related damage, as metabolic activity in the liver contributes substantially to heat production (
      • Jardine D.S.
      Heat illness and heat stroke.
      ). Oral temperature, although easier to access, does not accurately reflect core temperature due to such factors as probe placement, ingestion of hot or cold fluids, and exposure to ambient air (
      • Mazerolle S.M.
      • Ganio M.S.
      • Casa D.J.
      • et al.
      Is oral temperature an accurate measurement of deep body temperature? A systematic review.
      ).
      In the evaluation of hypothermia, measurement of rectal temperature is the most commonly used method. Here also, rectal temperatures lag changes in core temperature, which is more accurately assessed by esophageal probes (
      • Giesbrecht G.G.
      Cold stress, near drowning and accidental hypothermia: a review.
      ). Rectal thermometers used to assess hypothermia should be capable of giving accurate readings at temperatures below 34 °C (
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ). Although in cold environments oral, tympanic membrane, and axillary thermometers exposed to air temperatures cannot diagnose hypothermia, they can rule it out if the measured temperature is above 35 °C (
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ).
      In the evaluation of children, less intrusive methods have been studied extensively. Axillary thermometry compares favorably to rectal measurement in newborns (
      • Charafeddine L.
      • Tamim H.
      • Hassouna H.
      • et al.
      Axillary and rectal thermometry in the newborn: do they agree?.
      ) but is inaccurate in children and adults (
      • El-Radhi A.S.
      • Patel S.
      An evaluation of tympanic thermometry in a paediatric emergency department.
      ). Infrared tympanic thermometry provides reasonably accurate estimates of core temperatures in children older than 5 years and adults and is useful in settings where ease and speed of use are important (
      • Gasim G.I.
      • Musa I.R.
      • Abdien M.T.
      • Adam I.
      Accuracy of tympanic temperature measurement using an infrared tympanic membrane thermometer.
      ,
      • Apa H.
      • Gözmen S.
      • Bayram N.
      • et al.
      Clinical accuracy of tympanic thermometer and noncontact infrared skin thermometer in pediatric practice: an alternative for axillary digital thermometer.
      ,
      • Edelu B.O.
      • Ojinnaka N.C.
      • Ikefuna A.N.
      Fever detection in under 5 children in a tertiary health facility using the infrared tympanic thermometer in the oral mode.
      ,
      • Jefferies S.
      • Weatherall M.
      • Young P.
      • Beasley R.A.
      A systematic review of the accuracy of peripheral thermometry in estimating core temperatures among febrile critically ill patients.
      ,
      • Cabanac M.
      • Germain M.
      • Brinnel H.
      Tympanic temperatures during hemiface cooling.
      ). Infrared tympanic thermometry has limited accuracy, however, as it measures the average temperature not only of the tympanic membrane but also the air within the external auditory canal and heat radiated from the inner canal wall. To reduce the influence of air on aural temperature measurement, a cotton ball may be inserted into the aural canal to insulate the probe from the environment (
      • Giesbrecht G.G.
      Cold stress, near drowning and accidental hypothermia: a review.
      ). Additionally, cerumen may occlude the sensor's view of the tympanic membrane, and some device manufacturers add a correction factor that may not be valid for all conditions (
      • Jefferies S.
      • Weatherall M.
      • Young P.
      • Beasley R.A.
      A systematic review of the accuracy of peripheral thermometry in estimating core temperatures among febrile critically ill patients.
      ,
      • Edelu B.O.
      • Ojinnaka N.C.
      • Ikefuna A.N.
      Fever detection in under 5 children in a tertiary health facility using the infrared tympanic thermometer in the oral mode.
      ,
      • Craig J.V.
      • Lancaster G.A.
      • Taylor S.
      • et al.
      Infrared ear thermometry compared with rectal thermometry in children: a systematic review.
      ). Insufficient agreement of infrared tympanic thermometry with rectal thermometry across a series of comparison studies has led some authors to recommend against its use in situations where precise measurement of body temperature is needed (
      • Zhen C.
      • Xia Z.
      • Long L.
      • Pu Y.
      Accuracy of infrared ear thermometry in children: a meta-analysis and systematic review.
      ,
      • Huggins R.
      • Glaviano N.
      • Negishi N.
      • et al.
      Comparison of rectal and aural core body temperature thermometry in hyperthermic, exercising individuals: a meta-analysis.
      ,
      • Casa D.J.
      • Becker S.M.
      • Ganio M.S.
      • et al.
      Validity of devices that assess body temperature during outdoor exercise in the heat.
      ,
      • Craig J.V.
      • Lancaster G.A.
      • Taylor S.
      • et al.
      Infrared ear thermometry compared with rectal thermometry in children: a systematic review.
      ,
      • Nierman D.M.
      Core temperature measurement in the intensive care unit.
      ).
      Temporal artery thermometry has been shown in comparison studies to provide accuracy superior to that of other noninvasive methods in a variety of clinical settings (
      • Reynolds M.
      • Bonham L.
      • Gueck M.
      • et al.
      Are temporal artery temperatures accurate enough to replace rectal temperature measurement in pediatric ED patients?.
      ,
      • Allegaert K.
      • Casteels K.
      • van Gorp I.
      • Bogaert G.
      Tympanic, infrared skin, and temporal artery scan thermometers compared with rectal measurement in children: a real-life assessment.
      ,
      • Batra P.
      • Goyal S.
      Comparison of rectal, axillary, tympanic, and temporal artery thermometry in the pediatric emergency room.
      ,
      • Greenes D.S.
      • Fleisher G.R.
      Accuracy of a noninvasive temporal artery thermometer for use in infants.
      ). Its diagnostic accuracy was lower in children younger than 5 years and in febrile adults (
      • Bodkin R.P.
      • Acquisto N.M.
      • Zwart J.M.
      • Toussaint S.P.
      Differences in noninvasive thermometer measurements in the adult emergency department.
      ,
      • Odinaka K.K.
      • Edelu B.O.
      • Nwolisa C.E.
      • et al.
      Temporal artery thermometry in children younger than 5 years: a comparison with rectal thermometry.
      ,
      • Penning C.
      • van der Linden J.H.
      • Tibboel D.
      • Evenhuis H.M.
      Is the temporal artery thermometer a reliable instrument for detecting fever in children?.
      ).
      Whereas core temperature is a useful objective measurement to define the boundaries of hazardous divergence from normothermia and to monitor clinical changes, it is important to remember that temperature is only a guide and not the endpoint of medical assessment. More important is the physiologic state of the patient. In both hyperthermic and hypothermic patients the cardinal signal of illness is a change in mental status (
      • Santelli J.
      • Sullivan J.M.
      • Czarnik A.
      • Bedolla J.
      Heat illness in the emergency department: keeping your cool.
      ,
      • Atha W.F.
      Heat-related illness.
      ,
      • Jardine D.S.
      Heat illness and heat stroke.
      ,
      • Giesbrecht G.G.
      Cold stress, near drowning and accidental hypothermia: a review.
      ).

      3. Measurement of sweating

      Anhidrosis, or the absence of sweating, is not easily assessed by the patient's history alone unless it is extensive enough to cause heat intolerance or so markedly asymmetric that it is noticeable to the patient (
      • Cheshire W.P.
      • Kuntz N.L.
      Clinical evaluation of the patient with an autonomic disorder.
      ). The patient who used to sweat profusely during exposure to hot weather or when exercising vigorously but whose skin now remains dry under those conditions may be suspected to have widespread anhidrosis (
      • Cheshire W.P.
      • Kuntz N.L.
      Clinical evaluation of the patient with an autonomic disorder.
      ,
      • Cheshire W.P.
      • Freeman R.
      Disorders of sweating.
      ).
      At the bedside, loss of sweating is usually inapparent unless the patient is in a hot environment. Changes in baseline resting sweat activity can be quite subtle. Asymmetric sweating loss, such as hemibody, regional or distal anhidrosis, is more easily discerned by palpating than visualizing the skin, as the texture of dry skin is less smooth (
      • Cheshire W.P.
      • Kuntz N.L.
      Clinical evaluation of the patient with an autonomic disorder.
      ).
      A number of laboratory tests are available for more sensitive and precise clinical evaluation of sudomotor function (
      • Illigens B.M.
      • Gibbons C.H.
      Sweat testing to evaluate autonomic function.
      ). These rely on measuring a change in electrical conductance, a color change in an indicator dye, a sweat imprint on a soft medium, or dynamic recording by a humidity sensor of sweat evoked by an axon reflex in response to iontophoresis of a cholinergic agonist (Table 2).
      Table 2Comparison of methods of measuring sweating.
      MethodAdvantagesDisadvantages
      Bedside examinationRequires no special equipmentInsensitive, particularly in a cool environment
      Sympathetic skin responseEasily recorded with standard nerve conduction equipmentResponses are highly variable and attenuate with repeated stimulation

      Evaluates emotional more than thermoregulatory sweating
      Thermoregulatory sweating testEvaluates central and peripheral limbs of the thermoregulatory response

      Sensitive measure of the anatomical distribution of sweating and anhidrosis over the anterior body surface

      Evaluates the degree of anhidrosis as an indicator of susceptibility to heat stress

      Useful in evaluating both proximal and distal small fiber neuropathies

      Useful in diagnosing thoracic radiculopathy

      Useful in assessing anhidrosis following surgical sympathectomy
      May not distinguish a central from a peripheral sudomotor deficit

      Messy, patient must shower to remove indicator dye

      Time-consuming to perform

      Requires bulky, specialized equipment and a dedicated room

      Anticholinergic medications can confound interpretation
      Silastic imprint testEvaluates the number, volume, and anatomic distribution of droplets from individual sweat glands

      Equipment is fairly simple

      Safe and well-tolerated
      Time-consuming to analyze results
      Quantitative sudomotor axon reflex testSpecifically evaluates the functional integrity of postganglionic sudomotor nerves

      Sensitive and reproducible in the evaluation of small fiber neuropathy
      Mildly uncomfortable

      Anticholinergic medications can confound interpretation
      Epidermal biopsySensitive and reproducible in the evaluation of small fiber neuropathy

      Results are not confounded by medications
      Invasive, requires punch biopsy of skin

      Mild local infection occurs rarely

      3.1 Sympathetic skin response

      The sympathetic skin response consists of a momentary change of the electrical potential of the skin, which may be spontaneous or reflexively evoked by a variety of psychological stimuli (
      • Vetrugno R.
      • Liguori R.
      • Cortelli P.
      • Montagna P.
      Sympathetic skin response: basic mechanisms and clinical applications.
      ). This response is most easily recorded in the palms and soles, where sweating is controlled more by cortical than by hypothalamic processes and hence does not play a significant thermoregulatory role (
      • Quinton P.M.
      Sweating and its disorders.
      ). Although simple to measure, this response has great variability as well as limited sensitivity and specificity in the diagnosis of autonomic neuropathies (
      • Arunodaya G.R.
      • Taly A.B.
      Sympathetic skin response: a decade later.
      ,
      • Gutrecht J.A.
      Sympathetic skin response.
      ,
      • Maselli R.A.
      • Jaspan J.B.
      • Soliven B.C.
      • et al.
      Comparison of sympathetic skin response with quantitative sudomotor axon reflex test in diabetic neuropathy.
      ,
      • Niakan E.
      • Harati Y.
      Sympathetic skin response in diabetic peripheral neuropathy.
      ).

      3.2 Thermoregulatory sweating test

      Anatomic patterns of anhidrosis may be evaluated by the thermoregulatory sweating test (TST), which is a modification of Guttmann's quinizarin sweat test (
      • Guttmann L.
      The management of the quinizarin sweat test (Q.S.T.).
      ). The patient rests supine and unclothed on a movable cart within an enclosed cabinet, inside of which the temperature and humidity are carefully controlled, while the patient's skin and oral temperatures are continuously monitored. The heat is adjusted to induce a gradual rise in core temperature over 40 to 60 min to a target of 38.0 °C, which results in a maximal thermoregulatory sweating response (
      • Fealey R.D.
      • Low P.A.
      • Benarroch E.E.
      Thermoregulatory sweat test.
      ). Sweating over the anterior body surface is visualized by applying an indicator powder, such as corn starch mixed with alizarin red, which changes from yellow to purple when wet (
      • Fealey R.D.
      • Low P.A.
      • Benarroch E.E.
      Thermoregulatory sweat test.
      ).
      The TST has been shown to be a sensitive measure of the distribution of thermoregulatory sweating over the anterior body surface (
      • Fealey R.D.
      • Low P.A.
      • Thomas J.E.
      Thermoregulatory sweating abnormalities in diabetes mellitus.
      ,
      • Low V.A.
      • Sandroni P.
      • Fealey R.D.
      • Low P.A.
      Detection of small fiber neuropathy by sudomotor testing.
      ). The result indicates the surface area that is recruited to sweat but not the volume of sweat produced (
      • Fealey R.D.
      • Low P.A.
      • Benarroch E.E.
      Thermoregulatory sweat test.
      ). The area that lacks sweating may be expressed quantitatively as the percent anhidrosis (
      • Fealey R.D.
      • Low P.A.
      • Benarroch E.E.
      Thermoregulatory sweat test.
      ). The anatomical pattern of anhidrosis can suggest specific categories of thermoregulatory disorders. For example, distal anhidrosis is typical of length-dependent small fiber neuropathies (
      • Cheshire W.P.
      • Low P.A.
      Disorders of sweating and thermoregulation.
      ,
      • Low V.A.
      • Sandroni P.
      • Fealey R.D.
      • Low P.A.
      Detection of small fiber neuropathy by sudomotor testing.
      ). Segmental or regional zones of anhidrosis may reflect localized areas of sympathetic denervation as can be seen in thoracic radiculopathy, cholinergic neuropathy, harlequin syndrome, Ross syndrome, autoimmune autonomic ganglionopathy, or multiple system atrophy (
      • Cheshire W.P.
      • Low P.A.
      Disorders of sweating and thermoregulation.
      ,
      • Cheshire W.P.
      • Low P.A.
      Harlequin syndrome: still only half understood.
      ,
      • Cheshire W.P.
      • Freeman R.
      Disorders of sweating.
      ,
      • Fealey R.D.
      • Low P.A.
      • Thomas J.E.
      Thermoregulatory sweating abnormalities in diabetes mellitus.
      ). Extensive anhidrosis correlates with heat intolerance (
      • Mevorah B.
      • Frascarolo P.
      • Gianadda E.
      • Donatsch J.
      Sweat studies under conditions of moderate heat stress in two patients with the Nägeli-Franceschetti-Jadassohn syndrome.
      ).
      As a normal TST requires both central and peripheral limbs of the sweating response to be intact, the TST alone cannot distinguish between a central or peripheral sudomotor deficit. When combined with a test of peripheral sudomotor function, localizing power is greater (
      • Fealey R.D.
      • Low P.A.
      • Benarroch E.E.
      Thermoregulatory sweat test.
      ,
      • Cheshire W.P.
      • Low P.A.
      Disorders of sweating and thermoregulation.
      ).

      3.3 Silastic imprint test

      The presence and volume of sweat droplets may be sampled in particular skin regions by the silastic imprint test. Silastic impression material is spread over a small area of the skin surface, which is then stimulated iontophoretically with acetylcholine or pilocarpine. Once the silastic has hardened, impressions left by sweat droplets from individual eccrine glands are photographed and optically quantified to construct sweat histograms (
      • Stewart J.D.
      • Nguyen D.M.
      • Abrahamowicz M.
      Quantitative sweat testing using acetylcholine for direct and axon reflex mediated stimulation with silicone mold recording controls versus neuropathic diabetics.
      ,
      • Kennedy W.R.
      • Sakuta M.
      • Sutherland D.
      • Goetz F.C.
      Quantification of the sweating deficit in diabetes mellitus.
      ). A limitation of this method has been the presence of artifacts from hair, air bubbles, and variations in skin surface texture (
      • Illigens B.M.
      • Gibbons C.H.
      Sweat testing to evaluate autonomic function.
      ). Newer silicone materials have lessened some of these artifacts (
      • Vilches J.J.
      • Navarro X.
      New silicones for the evaluation of sudomotor function with the impression mold technique.
      ).
      A number of variations of this test have been developed. One is the dynamic sweat test, which utilizes digital video photography of pilocarpine-induced sweating through transparent tape powdered with corn starch to enhance visual contrast (
      • Provitera V.
      • Nolano M.
      • Caporaso G.
      • et al.
      Evaluation of sudomotor function in diabetes using the dynamic sweat test.
      ). Another is the quantitative direct and indirect test (QDIRT), which analyzes high-resolution digital photographs of silicone impressions of sweat droplets (
      • Gibbons C.H.
      • Illigens B.M.
      • Centi J.
      • Freeman R.
      QDIRT: quantitative direct and indirect test of sudomotor function.
      ).

      3.4 Quantitative sudomotor reflex test

      Anhidrosis caused by lesions at the level of the peripheral nerve may be evaluated by the quantitative sudomotor axon reflex test (QSART), which evaluates the postganglionic sudomotor axon (
      • Low P.A.
      • Sletten D.M.
      Laboratory evaluation of autonomic failure.
      ). Acetylcholine electrophoresis is applied to the skin surface at four standard limb sites: typically the forearm, proximal leg, distal leg, and foot. The iontophoresed acetylcholine activates the sudomotor axon terminal, generating an action potential, which then travels antidromically along the sudomotor axon, and upon reaching a branch point travels orthodromically to release endogenous acetylcholine from a nerve terminal adjacent to the initially stimulated terminal. The released acetylcholine traverses the neuroglandular junction and binds to M3 muscarinic receptors on eccrine sweat glands to evoke a sudomotor response. Sweat droplets are collected and evaporated in a capsule secured to the skin surface and piped to a hygrometer, which measures the sweat volume over time, which is typically 5 min of stimulation followed by 5 min of additional recording (
      • Low P.A.
      • Sletten D.M.
      Laboratory evaluation of autonomic failure.
      ,
      • Low P.A.
      • Caskey P.E.
      • Tuck R.R.
      • et al.
      Quantitative sudomotor axon reflex test in normal and neuropathic subjects.
      ).
      Under controlled conditions, which include a sufficiently warm skin surface and the absence of anticholinergic medications, the QSART has been shown to be sensitive and reproducible in healthy subjects (
      • Low P.A.
      • Caskey P.E.
      • Tuck R.R.
      • et al.
      Quantitative sudomotor axon reflex test in normal and neuropathic subjects.
      ) and in patients with axonal peripheral neuropathies (
      • Low P.A.
      • Caskey P.E.
      • Tuck R.R.
      • et al.
      Quantitative sudomotor axon reflex test in normal and neuropathic subjects.
      ,
      • Low P.A.
      • Zimmerman B.R.
      • Dyck P.J.
      Comparison of distal sympathetic with vagal function in diabetic neuropathy.
      ). Sudomotor volumes are approximately three times greater in men than in women and do not decrease with age (
      • Low P.A.
      • Caskey P.E.
      • Tuck R.R.
      • et al.
      Quantitative sudomotor axon reflex test in normal and neuropathic subjects.
      ). QSART has proved to be useful in diagnosing and monitoring autonomic postganglionic involvement in peripheral neuropathies (
      • Low V.A.
      • Sandroni P.
      • Fealey R.D.
      • Low P.A.
      Detection of small fiber neuropathy by sudomotor testing.
      ,
      • Vinik A.L.
      • Maser R.E.
      • Mitchell B.D.
      • Freeman R.
      Diabetic autonomic neuropathy.
      ,
      • Stewart J.D.
      • Low P.A.
      • Fealey R.D.
      Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes.
      ,
      • Low P.A.
      • Caskey P.E.
      • Tuck R.R.
      • et al.
      Quantitative sudomotor axon reflex test in normal and neuropathic subjects.
      ).

      3.5 Epidermal biopsy

      Structural assessment of sweat gland innervation is possible by evaluation of epidermal nerve fiber density. Distal leg skin biopsy with quantification of the linear density of intraepidermal nerve fibers has been shown to be a reliable method for the diagnosis of small fiber neuropathy (
      • Provitera V.
      • Gibbons C.H.
      • Wendelschafer-Crabb G.
      • et al.
      A multi-center, multinational age- and gender-adjusted normative dataset for immunofluorescent intraepidermal nerve fiber density at the distal leg.
      ,
      • Joint Task Force of the EFNS and the PNS
      European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.
      ). Loss of sweat gland nerve fiber density correlates well with anhidrosis by TST (
      • Loavenbruck A.
      • Wendelschaefer-Crabbe G.
      • Sandroni P.
      • Kennedy W.R.
      Quantification of sweat gland volume and innervation in neuropathy: correlation with thermoregulatory sweat testing.
      ) and with worsening peripheral neuropathy (
      • Lauria G.
      • Dacci P.
      • Lombardi R.
      • et al.
      Side and time variability of intraepidermal nerve fiber density.
      ,
      • Gibbons C.H.
      • Illigens B.M.
      • Wang N.
      • Freeman R.
      Quantification of sudomotor innervation: a comparison of three methods.
      ,
      • Gibbons C.H.
      • Freeman R.
      Antibody titers predict clinical features of autoimmune autonomic ganglionopathy.
      ,
      • Gibbons C.H.
      • Illigens B.M.
      • Wang N.
      • Freeman R.
      Quantification of sweat gland innervation: a clinical-pathologic correlation.
      ). With this technique mild localized skin infection has occurred at a frequency of 1.9: 1000 (
      • Joint Task Force of the EFNS and the PNS
      European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.
      ).

      4. Thermoregulatory disorders

      Disorders that impair thermoregulatory autonomic pathways may increase the risk of heat-related or cold-related illness. However, they do not always present in this way, as patients may retain sufficient thermoregulatory capacity to tolerate and remain normothermic in their particular environments. The clinical value of tests that detect even asymptomatic degrees of thermoregulatory impairment lies in the diagnostic and localizing information they provide in the evaluation of a variety of autonomic neurologic disorders.

      4.1 Small fiber neuropathies

      A prime example of a clinically important thermoregulatory deficit in a normothermic patient is small fiber neuropathy. Many peripheral neuropathies selectively or disproportionately affect autonomic fibers, including those which innervate eccrine glands (
      • Low P.A.
      • Sandroni P.
      The autonomic neuropathies.
      ). The aforementioned tests of sudomotor function are useful in the diagnosis and assessment of severity of distal small fiber neuropathies affecting sudomotor fibers and are particularly sensitive in comparison in detecting early or selectively small fiber neuropathies (
      • Illigens B.M.
      • Gibbons C.H.
      Sweat testing to evaluate autonomic function.
      ,
      • Cheshire W.P.
      • Low P.A.
      Disorders of sweating and thermoregulation.
      ,
      • Low P.A.
      • Zimmerman B.R.
      • Dyck P.J.
      Comparison of distal sympathetic with vagal function in diabetic neuropathy.
      ). Nerve conduction studies, which preferentially evaluate large myelinated nerve fibers, may be normal in patients with neuropathies that selectively affect small caliber unmyelinated fibers (
      • Low P.A.
      • Hilz M.J.
      Diabetic autonomic neuropathy.
      ,
      • Low V.A.
      • Sandroni P.
      • Fealey R.D.
      • Low P.A.
      Detection of small fiber neuropathy by sudomotor testing.
      ).
      In one series of 40 patients suspected of having distal small fiber neuropathy on the basis of symptoms of distal burning, hyperalgesia, and allodynia, QSART was abnormal in 80% of patients, TST was abnormal in 72% of patients, and one or both tests were abnormal in 90% of patients (
      • Stewart J.D.
      • Low P.A.
      • Fealey R.D.
      Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes.
      ). In another study of 125 patients with symptoms of distal small fiber neuropathy related to a variety of causes, but mostly idiopathic, QSART demonstrated length-dependent abnormalities in 74% of patients, TST showed distal anhidrosis in 59%, and one or both tests showed distal abnormalities in 93% of patients (
      • Low V.A.
      • Sandroni P.
      • Fealey R.D.
      • Low P.A.
      Detection of small fiber neuropathy by sudomotor testing.
      ). In patients with various types of distal small fiber neuropathy, the presence of QSART deficits agreed well with skin biopsies showing loss of epidermal C-fibers (
      • Singer W.
      • Spies J.M.
      • McArthur J.
      • et al.
      Prospective evaluation of somatic and autonomic small fibers in selected autonomic neuropathies.
      ,
      • Novak V.
      • Freimer M.L.
      • Kissel J.T.
      • et al.
      Autonomic impairment in painful neuropathy.
      ).
      Diabetic neuropathy is the most prevalent peripheral neuropathy in developed countries (
      • Low P.A.
      • Hilz M.J.
      Diabetic autonomic neuropathy.
      ). In a large, longitudinal, population-based study in Rochester, Minnesota, clinical manifestations of peripheral neuropathy were present in approximately 50% of diabetic patients, of which approximately 10% had a clinical autonomic neuropathy (
      • Dyck P.J.
      • Kratz K.M.
      • Karnes J.L.
      • et al.
      The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study.
      ,
      • Dyck P.J.
      • Karnes J.L.
      • O'Brien P.C.
      • et al.
      The Rochester Diabetic Neuropathy Study: reassessment of tests and criteria for diagnosis and staged severity.
      ). Distal anhidrosis was the most common pattern, with the proximal extent of anhidrosis progressing with the duration of neuropathy (
      • Fealey R.D.
      • Low P.A.
      • Thomas J.E.
      Thermoregulatory sweating abnormalities in diabetes mellitus.
      ).
      The differential diagnosis of nondiabetic small fiber sensory and autonomic neuropathies is extensive and encompasses acute and chronic, self-limited and progressive phenotypes. Small fiber neuropathies range from idiopathic, autoimmune, paraneoplastic, hereditary, toxic and drug-related, to degenerative in etiology and have been reviewed in detail elsewhere (
      • Gibbons C.H.
      Small fiber neuropathies.
      ,
      • Themistocleous A.C.
      • Ramirez J.D.
      • Serra J.
      • Bennett D.L.
      ,
      • Hoeijmakers J.G.
      • Faber C.G.
      • Lauria G.
      • et al.
      Small-fibre neuropathies—advances in diagnosis, pathophysiology and management.
      ,
      • Low P.A.
      • Sandroni P.
      The autonomic neuropathies.
      ). Notably, Sjögren syndrome commonly impairs sudomotor function and can cause generalized anhidrosis (
      • Fujita K.
      • Hatta K.
      Acquired generalized anhidrosis: review of the literature and report of a case with lymphocytic hidradenitis and sialadenitis successfully treated with cyclosporine.
      ,
      • Pavlakis P.P.
      • Alexopoulos H.
      • Kosmidis M.L.
      • et al.
      Peripheral neuropathies in Sjögren's syndrome: a critical update on clinical features and pathogenetic mechanisms.
      ).
      Autonomic ganglionic involvement should also be considered, particularly in acute or subacute presentations. Anhidrosis is among the clinical features of autoimmune autonomic ganglionopathy, which is characterized by antibodies against ganglionic α-3 acetylcholine receptors and typically presents with orthostatic hypotension, gastrointestinal dysmotility, bladder dysfunction, sicca symptoms, and impaired pupillary responses (
      • Winston N.
      • Vernino S.
      Recent advances in autoimmune autonomic ganglionopathy.
      ,
      • Gibbons C.H.
      • Freeman R.
      Antibody titers predict clinical features of autoimmune autonomic ganglionopathy.
      ,
      • Vernino S.
      • Hopkins S.
      • Wang Z.
      Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy.
      ).

      4.2 Disorders of the response to cold

      Many neurologic disorders can potentially impair the patient's response to cold (Table 3). Any disorder that restricts mobility, such as Parkinson's disease, stroke, spinal cord injury, or myopathy, may limit the ability to generate heat by muscle contraction or may delay efforts to reach shelter in cold weather (
      • Meiman J.
      • Anderson H.
      • Tomassallo C.
      • Centers for Disease Control and Prevention
      Hypothermia-related deaths—Wisconsin, 2014, and United States, 2003–2013.
      ). Additionally, neurologic disorders that impair the sensation of cold or cause inappropriate cutaneous vasodilatation, such as some peripheral neuropathies and myelopathies, may decrease thermoregulatory peripheral vasoconstriction or the awareness of a cold environment (
      • Petrone P.
      • Arsenio J.A.
      • Marini C.P.
      Management of accidental hypothermia and cold injury.
      ,
      • Brown D.J.A.
      • Brugger H.
      • Boyd J.
      • Paal P.
      Accidental hypothermia.
      ,
      • Tesfaye S.
      • Malik R.
      • Ward J.D.
      Vascular factors in diabetic neuropathy.
      ).
      Table 3Factors that may increase susceptibility to thermal illness.
      ConditionCold-related illnessHeat-related illness
      EnvironmentalExposure to extreme cold

      Prolonged exposure to mild cold

      Cold water immersion or submersion

      Exposure to cold air, ice, or snow

      Lack of shelter or insulating clothing

      Malnutrition
      Strenuous physical exercise in hot weather

      Summer heat waves

      Urban environments that retain heat

      Sequestration in hot parked automobiles

      Personal protective equipment that renders sweating ineffective
      General medicalHypoglycemia

      Diabetic ketoacidosis

      Hypothyroidism

      Adrenal failure

      Hypopituitarism

      Renal failure

      Shock

      Sepsis

      Anorexia nervosa
      Thyrotoxicosis

      Pheochromocytoma
      NeurologicalDisorders that impair judgment

       Dementia

       Head trauma

       Schizophrenia

       Hepatic encephalopathy

      Disorders that impair mobility

       Recent trauma

       Stroke

       Spinal cord injury

       Parkinson's disease

       Multiple system atrophy

       Myopathy

       Severe peripheral neuropathy

      Disorders that impair thermal sensation

       Peripheral neuropathy

      Disorders that may impair thermoregulatory responses

       Wernicke encephalopathy

       Stroke

       Spinal cord injury

       Guillain–Barré syndrome

       Amyotrophic lateral sclerosis

       Multiple sclerosis

       Myopathy
      Disorders that cause widespread anhidrosis

       Cholinergic neuropathy

       Autoimmune autonomic ganglionopathy

       Chronic idiopathic anhidrosis

       Botulism

       Generalized small fiber neuropathy

       Sjögren syndrome

       Multiple system atrophy

       Fabry's disease

       Bilateral cervical sympathectomy

      Disorders that increase thermogenesis

       Status epilepticus

       Neuroleptic malignant syndrome

       Malignant hyperthermia
      PharmacologicalAlcohol

      Sedatives

      Phenothiazines

      Opioids

      Clonidine

      Neuromuscular blocking agents

      General anesthetics
      Carbonic anhydrase inhibitors

      Anticholinergics

      Antihistamines

      Serotoninergics

      Psychomotor stimulants

      Diuretics
      Additionally, some central nervous system disorders, such as Wernicke's encephalopathy, may impair the generation of a thermoregulatory response in the hypothalamus (
      • Reuter J.B.
      • Girard D.E.
      • Cooney T.G.
      Current concepts. Wernicke's encephalopathy.
      ,
      • Kearsley J.H.
      • Musso A.F.
      Hypothermia and coma in the Wernicke-Korsakoff syndrome.
      ). Hypothermia has been described in the context of hypothalamic demyelination in multiple sclerosis (
      • Geny C.
      • Pradat P.F.
      • Yulis J.
      • et al.
      Hypothermia, Wernicke encephalopathy and multiple sclerosis.
      ). The epileptic patient who is postictal following a generalized seizure may be temporarily unable to withdraw from a cold environment. The risk of hypothermia is greater in those with dementia or who have consumed alcohol or sedative drugs that depress the sensorium (
      • Daulatzai M.A.
      Conversion of elderly to Alzheimer's dementia: role of confluence of hypothermia and senescent stigmata—the plausible pathway.
      ,
      • Turk E.E.
      Hypothermia.
      ). Additionally, drugs such as the opioid meperidine and the α-adrenergic antagonist clonidine inhibit shivering (
      • Cheshire W.P.
      Disorders of thermal regulation.
      ).
      Hypothermia does not typically occur in patients with hyperhidrosis, despite evaporative heat loss, unless the hyperhidrosis is unrelated to heat stress (
      • Cheshire W.P.
      • Fealey R.D.
      Drug-induced hyperhidrosis and hypohidrosis: incidence, prevention, and management.
      ). A notable exception is episodic spontaneous hypothermia with hyperhidrosis associated with agenesis of the corpus callosum (
      • Shapiro W.R.
      • Williams G.H.
      • Plum F.
      Spontaneous recurrent hypothermia accompanying agenesis of the corpus callosum.
      ). The latter feature appears not to be the causative basis for the hypothermia, as hypothermia occurs only in a small proportion of individuals with agenesis of the corpus callosum (
      • Pazderska A.
      • O'Connell M.
      • Pender N.
      • et al.
      Insights into thermoregulation: a clinico-radiological description of Shapiro syndrome.
      ), and cases of Shapiro syndrome without corpus callosum agenesis have been described (
      • Rodrigues Masruha M.
      • Lin J.
      • Arita J.H.
      • et al.
      Spontaneous periodic hypothermia and hyperhidrosis: a possibly novel cerebral neurotransmitter disorder.
      ,
      • Dundar N.O.
      • Boz A.
      • Duman O.
      • et al.
      Spontaneous periodic hypothermia and hyperhidrosis.
      ,
      • Sheth R.D.
      • Barron T.F.
      • Hartlage P.L.
      Episodic spontaneous hypothermia with hyperhidrosis: implications for pathogenesis.
      ). These patients do not shiver even during marked hypothermia (
      • Sheth R.D.
      • Barron T.F.
      • Hartlage P.L.
      Episodic spontaneous hypothermia with hyperhidrosis: implications for pathogenesis.
      ). Positron emission tomography in Shapiro syndrome has shown mild increases in metabolism in the tectal plate, posterior pons and medulla, and cerebellar vermis during hypothermic episodes (
      • Pazderska A.
      • O'Connell M.
      • Pender N.
      • et al.
      Insights into thermoregulation: a clinico-radiological description of Shapiro syndrome.
      ). Decreased cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid suggest that these patients may have decreased activity in central dopaminergic and serotonergic pathways (
      • Rodrigues Masruha M.
      • Lin J.
      • Arita J.H.
      • et al.
      Spontaneous periodic hypothermia and hyperhidrosis: a possibly novel cerebral neurotransmitter disorder.
      ).
      Additional risk factors for hypothermia include endocrine disorders such as hypothyroidism, hypoglycemia, and adrenal insufficiency, which impair metabolic thermogenesis (
      • Petrone P.
      • Arsenio J.A.
      • Marini C.P.
      Management of accidental hypothermia and cold injury.
      ,
      • Ulrich A.S.
      • Rathlev N.K.
      Hypothermia and localized cold injuries.
      ).

      4.3 Disorders of the response to heat

      Numerous medical conditions can predispose to heat exhaustion or nonexertional heat stroke (Table 3). These include autonomic disorders that cause widespread anhidrosis resulting in a compromised ability to liberate heat. Not all anhidrotic patients will experience heat-related illness, however, as anhidrosis may remain asymptomatic in the absence of heat stress (
      • Cheshire W.P.
      Disorders of thermal regulation.
      ).
      Widespread anhidrosis as the predominant clinical presentation is often due to a cholinergic neuropathy, which may be accompanied by other signs or symptoms of cholinergic failure such as sicca syndrome, abnormal pupillary light responses, or intestinal pseudo-obstruction (
      • Cheshire W.P.
      • Freeman R.
      Disorders of sweating.
      ). When the onset is acute or subacute, an autoimmune etiology should be considered. Antibodies to the ganglionic α-3 acetylcholine receptor are found in the sera of some patients (
      • Gibbons C.H.
      • Freeman R.
      Antibody titers predict clinical features of autoimmune autonomic ganglionopathy.
      ,
      • Kimpinski K.
      • Iodice V.
      • Sandroni P.
      • et al.
      Sudomotor dysfunction in autoimmune autonomic ganglionopathy.
      ,
      • Klein C.M.
      • Vernino S.
      • Lennon V.A.
      • et al.
      The spectrum of autoimmune autonomic neuropathies.
      ).
      Other cases are due to acquired idiopathic generalized anhidrosis, which is an immune-mediated disorder characterized by absence of sweating, urticaria, elevated IgE levels, atrophy and degeneration of the sweat glands, biopsies of which show infiltration by lymphocytes and mast cells (
      • Murakami K.
      • Sobue G.
      • Terao S.
      • Mitsuma T.
      Acquired idiopathic generalized anhidrosis: a distinctive clinical syndrome.
      ). Skin biopsies in some patients have shown occlusion of coiled ducts by an amorphous eosinophilic substance (
      • Ogino J.
      • Saga K.
      • Kagaya M.
      • et al.
      Idiopathic acquired generalized anhidrosis due to occlusion of proximal coiled ducts.
      ). In other cases of anhidrosis the sweat glands are morphologically normal, and microneurography shows intact bursts of skin sympathetic activity consistent with deficient cholinergic transmission (
      • Nakazato Y.
      • Tamura N.
      • Ohkuma A.
      • et al.
      Idiopathic pure sudomotor failure: anhidrosis due to deficits in cholinergic transmission.
      ). Anhidrosis in some of these patients responds to steroids (
      • Nakazato Y.
      • Tamura N.
      • Ohkuma A.
      • et al.
      Idiopathic pure sudomotor failure: anhidrosis due to deficits in cholinergic transmission.
      ).
      Another cholinergic neuropathy is Ross syndrome, which is characterized by the clinical triad of progressive segmental anhidrosis, Adie's tonic pupils, and areflexia (
      • Macefield V.G.
      Selective autonomic failure: Ross syndrome.
      ,
      • Xavier M.H.
      • Porto F.H.
      • Pereira G.B.
      • et al.
      Anhidrosis as the first sign of Ross syndrome.
      ,
      • Ross A.T.
      Progressive selective sudomotor denervation.
      ). The anhidrosis, which may be extensive enough to cause heat intolerance, often occurs asymmetrically adjacent to areas of preserved or compensatory sweating (
      • Xavier M.H.
      • Porto F.H.
      • Pereira G.B.
      • et al.
      Anhidrosis as the first sign of Ross syndrome.
      ,
      • Weller M.
      • Wilhelm H.
      • Sommer N.
      • et al.
      Tonic pupil, areflexia, and segmental anhidrosis: two additional cases of Ross syndrome and review of the literature.
      ). Pharmacologic and histopathological studies have indicated a postganglionic cholinergic neuronal deficit (
      • Perretti A.
      • Nolano M.
      • De Joanna G.
      • et al.
      Is Ross syndrome a dysautonomic disorder only? An electrophysiologic and histologic study.
      ,
      • Sommer C.
      • Lindelaub T.
      • Zillikens D.
      • et al.
      Selective loss of cholinergic sudomotor fibers causes anhidrosis in Ross syndrome.
      ,
      • Wolfe G.I.
      • Galetta S.L.
      • Teener J.W.
      • et al.
      Site of autonomic dysfunction in a patient with Ross's syndrome and postganglionic Horner's syndrome.
      ).
      Chronic idiopathic anhidrosis is a syndrome characterized by heat intolerance, in which patients become hot, flushed, dizzy, dyspneic, and weak in response to heat stress or exercise but do not sweat and is distinguished from generalized autonomic failure by the absence of orthostatic hypotension, somatic neuropathy, or other neurologic deficits (
      • Low P.A.
      • Fealey R.D.
      • Sheps S.G.
      • et al.
      Chronic idiopathic anhidrosis.
      ). Chronic idiopathic anhidrosis has been associated with hyperthermia and heat stroke (
      • Freeman R.
      • Louis D.N.
      Case 29-1994—a 32-year-old man with exercise-induced hyperthermia and acquired anhidrosis.
      ,
      • Dann E.J.
      • Berkman N.
      Chronic idiopathic anhydrosis—a rare cause of heat stroke.
      ).
      Various other autonomic neuropathies may also increase the potential for developing hyperthermia. Severe diabetic autonomic neuropathy with widespread involvement of proximal sudomotor fibers occasionally causes heat intolerance (
      • Low P.A.
      • Hilz M.J.
      Diabetic autonomic neuropathy.
      ,
      • Cheshire W.P.
      • Low P.A.
      Disorders of sweating and thermoregulation.
      ,
      • Dyck P.J.
      • Kratz K.M.
      • Karnes J.L.
      • et al.
      The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study.
      ). In a TST study of 51 patients with diabetic neuropathy, global anhidrosis was present in 16% (
      • Fealey R.D.
      • Low P.A.
      • Thomas J.E.
      Thermoregulatory sweating abnormalities in diabetes mellitus.
      ). Distal or generalized anhidrosis with heat intolerance may also occur along with xerostomia and xerophthalmia as part of an autonomic neuropathy in Sjögren syndrome (
      • Goto H.
      • Matsuo H.
      • Fukudome T.
      • et al.
      Chronic autonomic neuropathy in a patient with primary Sjögren's syndrome.
      ,
      • Wright R.A.
      • Grant I.A.
      • Low P.A.
      Autonomic neuropathy associated with sicca complex.
      ,
      • Katayama I.
      • Yokozeki H.
      • Nishioka K.
      Impaired sweating as an exocrine manifestation in Sjögren's syndrome.
      ). Generalized anhidrosis with heat intolerance frequently occurs in Fabry's disease, which is an x-linked receive disorder of lipid metabolism in which deficiency of α-galactosidase A results in the accumulation of ceramide trihexoside in vascular endothelial cells (
      • Germain D.P.
      Fabry disease.
      ,
      • Kato H.
      • Sato K.
      • Hattori S.
      • et al.
      Fabry's disease.
      ,
      • Kang W.H.
      • Chun S.I.
      • Lee S.
      Generalized anhidrosis associated with Fabry's disease.
      ). Patients who have undergone bilateral surgical cervical sympathectomy may become intolerant of heat, particularly if sudomotor innervation of the face is obliterated (
      • Santelli J.
      • Sullivan J.M.
      • Czarnik A.
      • Bedolla J.
      Heat illness in the emergency department: keeping your cool.
      ,
      • Cheshire W.P.
      Disorders of thermal regulation.
      ).
      Further, widespread anhidrosis is characteristic of both multiple system atrophy (
      • Iodice V.
      • Lipp A.
      • Ahlskog J.E.
      • et al.
      Autopsy confirmed multiple system atrophy cases: Mayo experience and the role of autonomic function tests.
      ,
      • Kihara M.
      • Sugenoya J.
      • Takahashi A.
      The assessment of sudomotor dysfunction in multiple system atrophy.
      ,
      • Cohen J.
      • Low P.
      • Fealey R.
      • et al.
      Somatic and autonomic function in progressive autonomic failure and multiple system atrophy.
      ) and pure autonomic failure (
      • Bannister R.
      • Ardill L.
      • Fentem P.
      Defective autonomic control of blood vessels in idiopathic orthostatic hypotension.
      ,
      • Fealey R.D.
      • Schirger A.
      • Thomas J.E.
      Orthostatic hypotension.
      ). Spinal cord transection impairs thermoregulatory sweating below the level of the lesion (
      • Downey J.A.
      • Huckaba C.E.
      • Kelley P.S.
      • et al.
      Sweating responses to central and peripheral heating in spinal man.
      ,
      • Huckaba C.E.
      • Frewin D.B.
      • Downey J.A.
      • et al.
      Sweating responses of normal, paraplegia, and anhidrotic subjects.
      ,
      • Seckendorf R.
      • Randall W.C.
      Thermal reflex sweating in normal and paraplegic man.
      ). Heat generation from the intense muscle contractions of an epileptic seizure may contribute to hyperthermia under existing conditions of external heat stress and may further complicate status epilepticus (
      • Betjemann J.P.
      • Lowenstein D.H.
      Status epilepticus in adults.
      ). Muscle rigidity in Parkinson's disease, by contrast, does not cause hyperthermia (
      • Gillman P.K.
      Neuroleptic malignant syndrome: mechanisms, interactions, and causality.
      ).
      Also at potential risk are patients taking drugs that inhibit sweating. Carbonic anhydrase inhibitors, such as topiramate, zonisamide, and acetazolamide, inhibit sweat production at the level of the secretory coil clear cell or apex of ductal cells (
      • de Carolis P.
      • Magnifico F.
      • Pierangeli G.
      • et al.
      Transient hypohidrosis induced by topiramate.
      ,
      • Ben-Zeev B.
      • Watemberg N.
      • Augarten A.
      • et al.
      Oligohydrosis and hyperthermia: pilot study of a novel topiramate adverse effect.
      ). There have been reports of carbonic anhydrase inhibitors causing transient hypohidrosis with heat intolerance in children, who are approximately ten times more susceptible to the drugs' hypohidrotic effect than are adults (
      • Incecik F.
      • Hergüner M.O.
      • Altunbaşak S.
      Hypohidrosis and hyperthermia during topiramate treatment in children.
      ,
      • Markowitz S.Y.
      • Robbins M.S.
      • Cascella C.
      • et al.
      Reversible hypohidrosis with topiramate therapy for chronic migraine.
      ,
      • Knudsen J.F.
      • Thambi L.R.
      • Kapcala L.P.
      • et al.
      Oligohydrosis and fever in pediatric patients treated with zonisamide.
      ,
      • Ben-Zeev B.
      • Watemberg N.
      • Augarten A.
      • et al.
      Oligohydrosis and hyperthermia: pilot study of a novel topiramate adverse effect.
      ,
      • de Carolis P.
      • Magnifico F.
      • Pierangeli G.
      • et al.
      Transient hypohidrosis induced by topiramate.
      ,
      • Arcas J.
      • Ferrer T.
      • Roche M.C.
      • et al.
      Hypohidrosis related to the administration of topiramate to children.
      ). Rarely, fatal heat stroke has been described in association with topiramate therapy (
      • Borron S.W.
      • Woolard R.
      • Watts S.
      Fatal heat stroke associated with topiramate therapy.
      ).
      Other common examples of drugs that inhibit sweating include M3 anticholinergic agents, which include bladder antispasmodics, tricyclic antidepressants, and neuroleptics (
      • Lee C.P.
      • Chen P.J.
      • Chang C.M.
      Heat stroke during treatment with olanzapine, trihexyphenidyl, and trazodone in a patient with schizophrenia.
      ,
      • Gillman P.K.
      Neuroleptic malignant syndrome: mechanisms, interactions, and causality.
      ,
      • Cheshire W.P.
      • Fealey R.D.
      Drug-induced hyperhidrosis and hypohidrosis: incidence, prevention, and management.
      ,
      • Adubofour K.O.
      • Kajiwara G.T.
      • Goldberg C.M.
      • King-Angell J.L.
      Oxybutynin-induced heatstroke in an elderly patient.
      ,
      • Hermesh H.
      • Shiloh R.
      • Epstein Y.
      • et al.
      Heat intolerance in patients with chronic schizophrenia maintained with antipsychotic drugs.
      ,
      • Clark W.G.
      • Lipton J.M.
      Drug-related heatstroke.
      ). These drugs block the binding of acetylcholine to the M3 receptor at the neurocrine junction, which prevents the influx of extracellular calcium that triggers the efflux of potassium and chloride ions responsible for isotonic fluid egress from the luminal side of the clear cell (
      • Low P.A.
      • Opfer-Gehrking T.L.
      • Kihara M.
      In vivo studies on receptor pharmacology of the human eccrine sweat gland.
      ). Intoxication with drugs, such as salicylate and methylsalicylate, that uncouple oxidative phosphorylation also can cause hyperthermia (
      • Clark W.G.
      • Lipton J.M.
      Drug-related heatstroke.
      ).
      Hyperthermia is one of the cardinal signs of serotonin syndrome, the others being agitation, tremor, myoclonus, muscle rigidity, hyperreflexia, and hyperhidrosis. This dose-related, potentially fatal syndrome occurs in patients taking serotonin-selective reuptake inhibitors multiply or in combination with other drugs, such as meperidine, fentanyl, or tramadol, that enhance the availability of serotonin in the brain (
      • Paden M.S.
      • Franjic L.
      • Halcomb S.E.
      Hyperthermia caused by drug interactions and adverse reactions.
      ). The mechanism of hyperthermia and sweating is uncertain but may involve a direct effect on hypothalamic 5-HT receptors (
      • Marcy T.R.
      • Britton M.L.
      Antidepressant-induced sweating.
      ).
      Recreational abuse of psychomotor stimulants, such as cocaine, amphetamine, methamphetamine (METH), 3,4-methylenedioxy-methamphetamine (MDMA or “ecstasy”), or heroin, frequently cause hyperthermia. In the United States, stimulant drugs resulted in 93,562 emergency room visits in 2009 (
      • National Institute on Drug Abuse (NINDA)
      Drug-related Hospital Emergency Room Visits.
      ). Elevated body temperature is a nearly universal presenting sign in such cases (
      • Matsumoto R.r.
      • Seminerio M.J.
      • Turner R.C.
      • et al.
      Methamphetamine-induced toxicity: an updated review on issues related to hyperthermia.
      ). The mechanisms of hyperthermia have not been fully elucidated but likely involve a combination of central and peripheral effects. Exposure to these drugs causes the release of dopamine, serotonin, and norepinephrine in the central nervous system, with a direct effect on brain areas involved in thermoregulation, such as the hypothalamus, on which are located α1 and β adrenoreceptors. In support of this hypothesis is the finding that propranolol prevents methamphetamine-induced hyperthermia in laboratory mice (
      • Albers D.S.
      • Sonsalla P.K.
      Methamphetamine-induced hyperthermia and dopaminergic neurotoxicity in mice: pharmacological profile of protective and nonprotective agents.
      ). Evidence for a peripheral effect includes the observation that methamphetamine-induced hyperthermia in laboratory rats is prevented by sympathectomy or adrenalectomy, which suggests that stimulant release of norepinephrine from sympathetic nerve terminals increases thermogenesis in skeletal muscles under the influence of glucocorticoids (
      • Makisumi T.
      • Yoshida K.
      • Watanabe T.
      • et al.
      Sympatho-adrenal involvement in methamphetamine-induced hyperthermia through skeletal muscle hypermetabolism.
      ). Contributing mechanisms to ensuing hyperthermia may include activation of astrocytes and microglia, peripheral catecholamine release, increased skeletal muscle metabolism, tachycardia, hypertension, peripheral vasoconstriction, and cytokine formation and release (
      • Matsumoto R.r.
      • Seminerio M.J.
      • Turner R.C.
      • et al.
      Methamphetamine-induced toxicity: an updated review on issues related to hyperthermia.
      ,
      • Kiyatkin E.A.
      The hidden side of drug action: brain temperature changes induced by neuroactive drugs.
      ,
      • Kiyatkin E.A.
      Brain hyperthermia as physiological and pathological phenomena.
      ).
      Additionally, psychomotor stimulants acutely raise brain metabolism by increasing the release of monoamine neurotransmitters, which can cause pathological brain hyperthermia (brain temperature > 40 °C) that exceeds systemic hyperthermia (
      • Matsumoto R.r.
      • Seminerio M.J.
      • Turner R.C.
      • et al.
      Methamphetamine-induced toxicity: an updated review on issues related to hyperthermia.
      ,
      • Kiyatkin E.A.
      The hidden side of drug action: brain temperature changes induced by neuroactive drugs.
      ,
      • Kiyatkin E.A.
      Brain hyperthermia as physiological and pathological phenomena.
      ). When combined with potentially hyperthermic environmental conditions such as heat and exercise, amphetamine-like stimulants can induce heat stroke (
      • Matsumoto R.r.
      • Seminerio M.J.
      • Turner R.C.
      • et al.
      Methamphetamine-induced toxicity: an updated review on issues related to hyperthermia.
      ,
      • Kiyatkin E.A.
      The hidden side of drug action: brain temperature changes induced by neuroactive drugs.
      ,
      • Kiyatkin E.A.
      Brain hyperthermia as physiological and pathological phenomena.
      ). This tragic fact was highlighted by the death of 29-year-old British cyclist Tom Simpson while competing in the 1967 Tour de France. The outdoor temperature that day reached a sweltering 54 °C. Simpson collapsed during his approach of the summit of Ventoux, and resuscitation efforts were unsuccessful. On his body were found two empty tubes and a half-full one of amphetamine, the use of which at the time was legal in professional cycling (
      • Fotheringham W.
      Put Me Back on My Bike: In Search of Tom Simpson.
      ).
      Another cause of hyperthermia is neuroleptic malignant syndrome, which is a potentially fatal, idiosyncratic condition that occurs in 0.2% of patients taking dopamine 2 receptor antagonists, particularly haloperidol, aripiprazole, or flupentixol (
      • Su Y.P.
      • Chang C.K.
      • Hayes R.D.
      • et al.
      Retrospective chart review on exposure to psychotropic medications associated with neuroleptic malignant syndrome.
      ,
      • Perry P.J.
      • Wilborn C.A.
      Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management.
      ). Hyperthermia resulting from acute lithium intoxication has also been described (
      • Gill J.
      • Singh H.
      • Nugent K.
      Acute lithium intoxication and neuroleptic malignant syndrome.
      ). Clinical signs consist of hyperthermia, rigidity, hyperhidrosis, tachycardia, labile blood pressure, tremor, dysarthria, and delirium that progress over hours to days. Laboratory findings typically include elevations in creatine kinase, liver enzymes, and white blood count combined with low serum iron (
      • Perry P.J.
      • Wilborn C.A.
      Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management.
      ,
      • Rusyniak D.E.
      • Sprague J.E.
      Hyperthermic syndromes induced by toxins.
      ). Although its major feature of muscle rigidity seems to suggest that the hyperthermia results from a hypermetabolic state, the degree of muscle contraction is insufficient to induce hyperthermia (
      • Gillman P.K.
      Neuroleptic malignant syndrome: mechanisms, interactions, and causality.
      ). Central dopaminergic impairment with defective heat dissipation has been proposed to explain the hyperthermia (
      • Di Rossa A.E.
      • Morgante L.
      • Coraci M.A.
      • et al.
      Functional hyperthermia due to central dopaminergic impairment.
      ).
      Malignant hyperthermia is an autosomal dominantly inherited disorder of skeletal muscle calcium regulation that in up to 70% of cases is associated with mutations of the RYR1 gene encoding ryanodine receptor type 1 (
      • Gomez C.R.
      Disorders of body temperature.
      ,
      • Larach M.G.
      • Brandom B.W.
      • Allen G.C.
      • et al.
      Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007–2012: a report from the North American malignant hyperthermia registry of the malignant hyperthermia association of the United States.
      ,
      • Rosenberg H.
      • Davis M.
      • James D.
      • et al.
      Malignant hyperthermia.
      ,
      • Rusyniak D.E.
      • Sprague J.E.
      Hyperthermic syndromes induced by toxins.
      ). Approximately 1% result from mutations of CACNA1S, which encodes a skeletal muscle calcium channel. Upon exposure to volatile anesthetic agents, either alone or in combination with a depolarizing muscle relaxant, genetically predisposed individuals develop uncontrolled skeletal muscle hypermetabolism causing hyperthermia, muscle rigidity, tachycardia, acidosis, and hyperkalemia. Rhabdomyolysis with subsequent elevation in creatine kinase may lead to renal failure (
      • Larach M.G.
      • Brandom B.W.
      • Allen G.C.
      • et al.
      Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007–2012: a report from the North American malignant hyperthermia registry of the malignant hyperthermia association of the United States.
      ,
      • Rosenberg H.
      • Davis M.
      • James D.
      • et al.
      Malignant hyperthermia.
      ).

      5. Hypothermia

      Acute exposure to cold causes peripheral vasoconstriction, shivering, and increased metabolic heat production (
      • Castellani J.W.
      • Young A.J.
      • Ducharme M.B.
      • et al.
      American College of Sports Medicine position stand: prevention of cold injuries during exercise.
      ), as well as attenuation of thirst (
      • Kenefick R.W.
      • Hazzard M.P.
      • Mahood N.V.
      • et al.
      Thirst sensations and AVP responses at rest and during exercise-cold exposure.
      ). Acute cold stress also reduces plasma volume and increases urine flow rate (
      • Castellani J.W.
      • Young A.J.
      • Ducharme M.B.
      • et al.
      American College of Sports Medicine position stand: prevention of cold injuries during exercise.
      ). The predominant mechanism of this so-called cold-induced diuresis is redistribution of plasma volume from the periphery to the central circulation in response to peripheral vasoconstriction (
      • Freund B.J.
      • Sawka M.H.
      Influence of cold stress on human fluid balance.
      ,
      • Vogelaere P.
      • Savourey G.
      • Deklunder G.
      • et al.
      Reversal of cold induced haemoconcentration.
      ,
      • Lennquist S.
      • Granberg P.O.
      • Wedin B.
      Fluid balance and physical work capacity in humans exposed to cold.
      ). Cold-induced diuresis is attenuated in trained athletes (
      • Yoshida T.
      • Nagashima K.
      • Nakai S.
      • et al.
      Attenuation of urinary sodium excretion during cold-air exposure in trained athletes.
      ) and does not appear to be explained adequately by inhibition of release of arginine vasopressin (
      • Freund B.J.
      • Sawka M.H.
      Influence of cold stress on human fluid balance.
      ,
      • Hynynen M.
      • Ilmarinen R.
      • Tikkanen I.
      • Fyhrquist F.
      Plasma atrial natriuretic factor during cold-induced diuresis.
      ).
      Hypothermia is defined as a core body temperature of <35.0 °C (
      • Petrone P.
      • Arsenio J.A.
      • Marini C.P.
      Management of accidental hypothermia and cold injury.
      ,
      • Cheshire W.P.
      Disorders of thermal regulation.
      ,
      • Polderman K.H.
      Mechanisms of action, physiological effects, and complications of hypothermia.
      ,
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ,
      • Jurkovich G.J.
      Environmental cold-induced injury.
      ,
      • Ulrich A.S.
      • Rathlev N.K.
      Hypothermia and localized cold injuries.
      ,
      • Giesbrecht G.G.
      Cold stress, near drowning and accidental hypothermia: a review.
      ). As heat loss occurs more rapidly than heat production in the human body, any situation that promotes heat loss can hasten the onset of hypothermia (
      • Ulrich A.S.
      • Rathlev N.K.
      Hypothermia and localized cold injuries.
      ). Approximately 60% of heat is lost through radiation, 10–15% through conduction and convection, and 25–30% through evaporation and respiratory expiration (
      • Ulrich A.S.
      • Rathlev N.K.
      Hypothermia and localized cold injuries.
      ). In the United States, there are on average more than 1300 deaths per year from hypothermia, which is approximately twice the number of deaths annually as for exposure to heat (
      • Meiman J.
      • Anderson H.
      • Tomassallo C.
      • Centers for Disease Control and Prevention
      Hypothermia-related deaths—Wisconsin, 2014, and United States, 2003–2013.
      ).

      5.1 Causes of hypothermia

      Hypothermia occurs following prolonged exposure to cold, wet, or windy conditions once the body's ability to maintain a normothermic core temperature is overwhelmed. Factors that can predispose to hypothermia include winter sports activities, cold water immersion, or lack of sufficiently warm clothing or shelter from environmental cold weather (
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ,
      • Jurkovich G.J.
      Environmental cold-induced injury.
      ). Neonates and the elderly are at increased risk as they are less able to generate heat by shivering or preserve heat by vasoconstriction. Children generate more metabolic heat than adults, which is usually sufficient to maintain body heat while exercising but not during prolonged rest (
      • Falk B.
      Effects of thermal stress during rest and exercise in the paediatric population.
      ). The risk of hypothermia is greater in those who are malnourished, alcoholic, mentally ill, septic, in shock, or whose mobility is limited by disability or recent injury, if they are less able to generate heat from muscle contraction or actively seek shelter (
      • Brown D.J.A.
      • Brugger H.
      • Boyd J.
      • Paal P.
      Accidental hypothermia.
      ,
      • Brändström H.
      • Eriksson A.
      • Giesbrecht G.
      • et al.
      Fatal hypothermia: an analysis from a sub-arctic region.
      ,
      • Jurkovich G.J.
      Environmental cold-induced injury.
      ,
      • Ulrich A.S.
      • Rathlev N.K.
      Hypothermia and localized cold injuries.
      ,
      • Biem J.
      • Koehncke N.
      • Classen D.
      • Dosman J.
      Out of the cold: management of hypothermia and frostbite.
      ). Hypothermia can occur even in warm environments under conditions that cause the body to lose more heat than it generates (
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ).
      Hypothermia is also induced intentionally in medical settings for its neuroprotectant effect following cardiac arrest, stroke, traumatic brain or spinal cord injury. Therapeutic hypothermia has reached an acceptable level of safety through the development of sophisticated cooling systems using thermocouples and feedback sensors that allow for precise control of core temperature and is an area of active research in critical care medicine (
      • Maznyczka A.M.
      • Gershlick A.H.
      Therapeutic hypothermia in patients with out-of-hospital arrest.
      ,
      • Sherman A.L.
      • Wang M.Y.
      Hypothermia as a clinical neuroprotectant.
      ,
      • Macleod M.R.
      • Petersson J.
      • Norrving B.
      • et al.
      Hypothermia for stroke: call to action 2010.
      ).

      5.2 Diagnosis of hypothermia

      Hypothermia classically is defined as mild, moderate, or severe according to core temperature but is best understood as a decrease in body temperature that causes signs of physiologic dysfunction (Table 4) (
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ,
      • Ulrich A.S.
      • Rathlev N.K.
      Hypothermia and localized cold injuries.
      ,
      • Durrer B.
      • Brugger H.
      • Syme D.
      • International Commission for Mountain Emergency Medicine
      The medical on-site treatment of hypothermia: ICAR-MEDCOM recommendation.
      ). These categories derive from correlations of body temperature measurements with clinical presentations of accidental hypothermia (
      • Brown D.J.A.
      • Brugger H.
      • Boyd J.
      • Paal P.
      Accidental hypothermia.
      ,
      • Giesbrecht G.G.
      Cold stress, near drowning and accidental hypothermia: a review.
      ) and induced hypothermia in the treatment of cardiac arrest, traumatic brain injury, and other medical conditions in the 1940s through the 1960s (
      • Polderman K.H.
      Mechanisms of action, physiological effects, and complications of hypothermia.
      ). In general, the physiologic state of the patient is more important to monitor than the temperature (
      • Giesbrecht G.G.
      Cold stress, near drowning and accidental hypothermia: a review.
      ).
      Table 4Clinical presentations of thermal illness.
      HypothermiaNormothermiaHyperthermia
      Severe (<28 °C)Moderate (28°–32 °C)Mild (32°–35 °C)37° ± 1 °CHeat exhaustionHeat stroke (>40.5 °C)
      Mental statusDelirium, hallucinations, coma, may mimic deathFatigue, agitation, confusion, hallucinations, lethargy, amnesia, paradoxical undressingImpaired judgment, amnesiaFatigue, thirst, irritabilityDelirium, confusion, hallucinations, coma
      CutaneousFrostbiteCold, edematousVasoconstriction followed by hyperemiaSweating, flushedFlushed, loss of sweating in classical, but not exertional, heat stroke
      CardiovascularBradycardia, spontaneous atrial or ventricular fibrillation, hypotension, asystole at <20 °CJ waves, atrial fibrillation, hypotensionTachycardia, PR and QT interval prolongation, hypertensionTachycardia, postural syncopeHeart failure, hypotension, myocardial injury
      RespiratoryHypopnea, pulmonary edema, apnea at <24 °CHypopnea, impaired cough reflexTachypnea
      MuscularHypotonia, rhabdomyolysisLoss of shivering, rigidityShiveringWeakness, cramps
      NeurologicDilated nonreactive pupils at <26 °C, stupor, areflexiaSluggish pupillary responses, hyporeflexia, ataxiaDysarthria, loss of fine motor skillsHeadache, dizziness, paresthesiaSeizures
      HepaticDecreased enzyme activityDecreased enzyme activityHepatic injury
      RenalOliguriaDiuresis, renal tubular acidosisDiuresis from decreased hypothalamic release of antidiuretic hormoneOliguriaMyoglobinuria, renal failure
      HematologicThrombocytopenia, disseminated intravascular coagulation, prolonged prothrombin timeDecreased platelet functionHemoconcentrationThrombocytopenia, disseminated intravascular coagulation, prolonged prothrombin time
      GastrointestinalPancreatitis, gastric erosionsNausea, vomitingIleus, gastric erosionsNausea, vomitingMucosal swelling, vomiting
      Signs of mild hypothermia (core temperature 35°–32 °C) may include vigorous shivering, lethargy, apathy, impairment of fine motor skills, cold extremities, polyuria, pallor, tachypnea, and tachycardia. With development of moderate hypothermia (core temperature 32°–28 °C), physical signs may include depression of respirations and pulse, slurred speech, further impairment of mental function, paradoxical undressing, gross impairment of motor control, cessation of shivering, cyanosis, muscle rigidity, mydriasis, atrial or ventricular cardiac dysrhythmias, bradycardia, decreased blood pressure, hypoventilation, hyporeflexia, and loss of consciousness. If severe hypothermia (core temperature < 28 °C) develops, the patient may present with hypotension, pulmonary congestion and edema, muscle rigidity, areflexia, oliguria, spontaneous ventricular fibrillation, cardiac arrest, and coma (
      • Durrer B.
      • Brugger H.
      • Syme D.
      • International Commission for Mountain Emergency Medicine
      The medical on-site treatment of hypothermia: ICAR-MEDCOM recommendation.
      ). The skin is cold to the touch, the pupils are dilated, and the pulse and respirations may be difficult to detect. Severe cases can mimic death. The clinical presentations of hypothermia, which are quite variable among patients, are reviewed in greater detail elsewhere (
      • Brown D.J.A.
      • Brugger H.
      • Boyd J.
      • Paal P.
      Accidental hypothermia.
      ,
      • Brändström H.
      • Eriksson A.
      • Giesbrecht G.
      • et al.
      Fatal hypothermia: an analysis from a sub-arctic region.
      ,
      • Cheshire W.P.
      Disorders of thermal regulation.
      ,
      • Polderman K.H.
      Mechanisms of action, physiological effects, and complications of hypothermia.
      ;
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ,
      • Jurkovich G.J.
      Environmental cold-induced injury.
      ,
      • Castellani J.W.
      • Young A.J.
      • Ducharme M.B.
      • et al.
      American College of Sports Medicine position stand: prevention of cold injuries during exercise.
      ,
      • Ulrich A.S.
      • Rathlev N.K.
      Hypothermia and localized cold injuries.
      ,
      • Giesbrecht G.G.
      Cold stress, near drowning and accidental hypothermia: a review.
      ,
      • Fischbeck K.H.
      • Simon R.P.
      Neurological manifestations of accidental hypothermia.
      ).
      When the core temperature cannot readily be measured, the Swiss staging system distinguishes among five levels of hypothermia: HT I with clear consciousness and shivering, HT II with impaired consciousness without shivering, HT III with unconsciousness, HT IV with apparent death, and HT V with death due to irreversible hypothermia (
      • Brown D.J.A.
      • Brugger H.
      • Boyd J.
      • Paal P.
      Accidental hypothermia.
      ,
      • Durrer B.
      • Brugger H.
      • Syme D.
      • International Commission for Mountain Emergency Medicine
      The medical on-site treatment of hypothermia: ICAR-MEDCOM recommendation.
      ).
      Frostbite is a severe form of localized cold-induced tissue injury that occurs when skin or deeper tissue temperature falls below −2 °C, at which point ice crystals form at the cellular level, resulting in cellular dysfunction or destruction and, during rewarming, microvascular occlusion (
      • Jurkovich G.J.
      Environmental cold-induced injury.
      ). Severity ranges from hyperemia with edema to blistering, hemorrhagic vesicles, tissue necrosis, and gangrene (
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ,
      • Jurkovich G.J.
      Environmental cold-induced injury.
      ).

      5.3 Management of hypothermia

      Prevention of hypothermia during exposure to cold environments includes wearing sufficiently warm clothing as well as education about the risk factors and how to recognize the early signs of hypothermia. Clothing requirements in cold weather depend on metabolic rate, ambient temperature, water exposure, and wind velocity (
      • Castellani J.W.
      • Young A.J.
      • Ducharme M.B.
      • et al.
      American College of Sports Medicine position stand: prevention of cold injuries during exercise.
      ). Heat loss can be minimized by wearing knit caps, balaclavas, headbands to cover the ears, and layering to adjust insulation as physical activity increases (
      • Castellani J.W.
      • Young A.J.
      • Ducharme M.B.
      • et al.
      American College of Sports Medicine position stand: prevention of cold injuries during exercise.
      ). Heightened surveillance of exercisers is advised when wind-chill temperatures are below −27 °C (
      • Castellani J.W.
      • Young A.J.
      • Ducharme M.B.
      • et al.
      American College of Sports Medicine position stand: prevention of cold injuries during exercise.
      ). Cold weather athletes should eat a well-balanced diet and replace fluid lost through sweating (
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ). In the routine hospital environment, perioperative warming measures are necessary to prevent the heat loss that otherwise would occur during general anesthesia, which temporarily abolishes central thermoregulatory control, muscle contraction, and peripheral vasoconstriction (
      • Horosz B.
      • Malec-Milewska M.
      Methods to prevent intraoperative hypothermia.
      ).
      Once hypothermia is recognized, prompt treatment is necessary to avert preventable death. Wet or damp clothing should be removed without delay, and the individual should be removed from wind or rain to a warm, dry, sheltered environment. Mild hypothermia is best managed with passive external warming using blankets or metaloplastic sheets that reflect heat. The head should be covered. All patients with hypothermia should be assumed to be dehydrated and receive supplemental fluids (
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ,
      • Jurkovich G.J.
      Environmental cold-induced injury.
      ,
      • Ulrich A.S.
      • Rathlev N.K.
      Hypothermia and localized cold injuries.
      ,
      • Delaney K.A.
      • Howland M.A.
      • Vassallo S.
      • Goldfrank L.R.
      Assessment of acid–base disturbances in hypothermia and their physiologic consequences.
      ,
      • Giesbrecht G.G.
      • Bristow G.K.
      • Uin A.
      • et al.
      Effectiveness of three field treatments for induced mild (33.0 degrees C) hypothermia.
      ). Friction massage should be avoided as this can exacerbate tissue damage from frostbite (
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ).
      Hypothermia is a condition of medical urgency. In addition to the measures for treating mild hypothermia, vital signs should be closely monitored. Any patient with suspected hypothermia who has signs of cardiac dysrhythmia should be moved gently to avoid precipitating paroxysmal ventricular fibrillation, as the myocardium is more sensitive to mechanical stimulation during deep hypothermia (
      • Polderman K.H.
      Mechanisms of action, physiological effects, and complications of hypothermia.
      ,
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ,
      • Ulrich A.S.
      • Rathlev N.K.
      Hypothermia and localized cold injuries.
      ). Peripheral pulses in hypothermic patients may be difficult to palpate. In situations where the EKG shows an organized cardiac electrical rhythm (other than fibrillation), cardiopulmonary resuscitation with chest compression is contraindicated, despite the absence of a palpable pulse, because chest compressions may convert an adequate perfusing rhythm to ventricular fibrillation (
      • Jurkovich G.J.
      Environmental cold-induced injury.
      ). The risk of ventricular fibrillation increases as core temperature in the severely hypothermic patient rises above 28 °C. Below that temperature, cardiac dysrhythmias tend to be refractory, for which reason resuscitative efforts should continue until the absence of electrographic cardiac activity is documented after the core temperature has risen to 28 °C–30 °C (
      • Petrone P.
      • Arsenio J.A.
      • Marini C.P.
      Management of accidental hypothermia and cold injury.
      ).
      Invasive active core warming methods may be indicated in patients with severe hypothermia. These methods include heated intravenous fluids, inhalation rewarming, or peritoneal lavage (
      • Danzi D.F.
      • Pozos R.S.
      Accidental hypothermia.
      ). Rewarming by hemodialysis has also been used and has the added benefit of treating accompanying hyperkalemia and renal failure. The most efficient (by an order of magnitude) method for rewarming is cardiopulmonary bypass or extracorporeal active core rewarming (CAVR), which is also the most invasive and is reserved for exceptionally severe cases in appropriately equipped medical settings (
      • Petrone P.
      • Arsenio J.A.
      • Marini C.P.
      Management of accidental hypothermia and cold injury.
      ,
      • Jurkovich G.J.
      Environmental cold-induced injury.
      ,
      • Giesbrecht G.G.
      Cold stress, near drowning and accidental hypothermia: a review.
      ). Antiarrhythmic drugs may be required (
      • Cappaert T.A.
      • Stone J.A.
      • Castellani J.W.
      • et al.
      National Athletic Trainers' Association position statement: environmental cold injuries.
      ,
      • Jurkovich G.J.
      Environmental cold-induced injury.
      ,
      • Ulrich A.S.
      • Rathlev N.K.
      Hypothermia and localized cold injuries.
      ,
      • Kornsberger E.
      • Schwarz B.
      • Lindner K.H.
      • Mair P.
      Forced air surface rewarming in patients with severe accidental hypothermia.
      ,
      • Walpoth B.H.
      • Walpoth-Aslan B.N.
      • Mattle H.P.
      • et al.
      Outcome of survivors of accidental deep hypothermia and circulatory arrest treated with extracorporeal blood warming.
      ,
      • Daanen H.A.
      • Van de Linde F.J.
      Comparison of four noninvasive rewarming methods for mild hypothermia.
      ,
      • Giesbrecht G.G.
      • Bristow G.K.
      • Uin A.
      • et al.
      Effectiveness of three field treatments for induced mild (33.0 degrees C) hypothermia.
      ). Severe hypothermia may exhibit afterdrop, which is a phenomenon in which heat-induced vasodilation in the arms and legs during external active rewarming with, for example, heating lamps sends a rush of relatively cold, acidic blood from the periphery to the core with the potential to trigger cardiac arrhythmias (
      • Petrone P.
      • Arsenio J.A.
      • Marini C.P.
      Management of accidental hypothermia and cold injury.
      ,
      • Ulrich A.S.
      • Rathlev N.K.
      Hypothermia and localized cold injuries.
      ). Active core rewarming methods avoid this problem (
      • Jurkovich G.J.
      Environmental cold-induced injury.
      ).

      6. Hyperthermia

      Hyperthermia classically is defined as a core body temperature of >40.5 °C (
      • McGeehin M.A.
      • Mirabelli M.
      The potential impacts of climate variability and change on temperature-related morbidity and mortality in the United States.
      ,
      • Clark W.G.
      • Lipton J.M.
      Drug-related heatstroke.
      ). Some experts accept a definition of >40 °C (
      • Atha W.F.
      Heat-related illness.
      ,
      • Jardine D.S.
      Heat illness and heat stroke.
      ,
      • Wexler R.K.
      Evaluation and treatment of heat-related illnesses.
      ). Core temperature alone, however, is inadequate, and the diagnosis of hyperthermia or heat stroke requires central nervous system dysfunction (
      • Santelli J.
      • Sullivan J.M.
      • Czarnik A.
      • Bedolla J.
      Heat illness in the emergency department: keeping your cool.
      ,
      • Atha W.F.
      Heat-related illness.
      ,
      • Jardine D.S.
      Heat illness and heat stroke.
      ). The temperature threshold is somewhat arbitrary and has been based on cumulative experience with patients evaluated for heat-related illness. Correlations between body temperature and clinical consequences of hyperthermia have been limited by the practical difficulty of obtaining accurate core temperature measurements in the field, underrecognition of potentially unsafe elevations in core temperature, individual differences in heat tolerance and susceptibility, and the spectrum of variations in heat stress presentations (
      • Sawka M.N.
      • Latzka W.A.
      • Montain S.J.
      • et al.
      Physiologic tolerance to uncompensable heat: intermittent exercise, field vs laboratory.
      ,
      • Clark W.G.
      • Lipton J.M.
      Drug-related heatstroke.
      ). More important than measured temperature is the clinical condition of the patient (
      • Anderson R.J.
      • Reed G.
      • Knochel J.
      ).
      Fever, which this review does not address specifically, is a subtype of hyperthermia consisting of a regulated elevation in core temperature in response to a pathological process, such as an infection, in which the thermoregulatory system continues to function adequately. Unlike the hyperpyrexia of fever, other forms of hyperthermia do not subside when treated with cyclo-oxygenase inhibitors (
      • Clark W.G.
      • Lipton J.M.
      Drug-related heatstroke.
      ).
      In the United States more than 600 deaths occur annually from hyperthermia (
      • Luber G.E.
      • Sanchez C.A.
      Heat-related deaths — United States, 1999–2003.
      ). During the years 1999–2003, a total of 3442 U.S. deaths resulting from exposure to extreme heat were reported, with an annual mean of 688 deaths. The cause of death was recorded as exposure to excessive heat in 2239 (65%), and for the remaining 1203 (35%) hyperthermia was recorded as a contributing factor (
      • Luber G.E.
      • Sanchez C.A.
      Heat-related deaths — United States, 1999–2003.
      ). Some years have seen much higher rates of heat stroke. In the United States, a severe heat wave in 1980 resulted in 1700 deaths (
      • Centers for Disease Control
      Heatstroke—United States, 1980.
      ). In Europe, a severe heat wave in August 2003 resulted in 14,800 heat-related deaths in Lyon, France (
      • Argaud L.
      • Ferry T.
      • Le Q.H.
      • et al.
      Short- and long-term outcomes of heatstroke following the 2003 heat wave in Lyon, France.
      ).
      These and other clusters of heat-related mortality during summer heat waves have raised medical and public awareness of heat stroke, which has improved recognition of vulnerable populations, such as the elderly, which have decreased capacity to dissipate heat or increased risk of dehydration (
      • Santelli J.
      • Sullivan J.M.
      • Czarnik A.
      • Bedolla J.
      Heat illness in the emergency department: keeping your cool.
      ,
      • Atha W.F.
      Heat-related illness.
      ,
      • Jardine D.S.
      Heat illness and heat stroke.
      ). Prognostic factors contributing to heat-related deaths include being confined to bed (OR 6.44), not leaving home daily (OR 3.35), being unable to care for oneself (OR 2.97), preexisting psychiatric disease (OR 3.61), cardiovascular disease (OR 2.48), and pulmonary disease (OR 1.61), whereas factors associated with more favorable outcomes included functioning air conditioning (OR 0.23), visiting cool environments (OR 0.34), increasing social contact (OR 0.40), taking extra showers or baths (OR 0.32), and using fans (OR 0.60) (
      • Bouchama A.
      • Dehbi M.
      • Mohamed G.
      • et al.
      Prognostic factors in heat wave related deaths: a meta-analysis.
      ).
      Brain cells and hepatic cells are exquisitely sensitive to hyperthermia. Irreversible neuronal damage begins at temperatures at or above 40 °C, which is only 3 °C above normal baseline, and progresses exponentially with further increases in temperature (
      • Kiyatkin E.A.
      Brain temperature homeostasis: physiological fluctuations and pathological shifts.
      ). Cerebellar Purkinje cells are particularly vulnerable to heat injury (
      • Kiyatkin E.A.
      Brain temperature homeostasis: physiological fluctuations and pathological shifts.
      ). Hyperthermia also increases blood–brain-barrier permeability, allowing entry of potentially neurotoxic metabolites and substances that in conditions of health are retained in the periphery (
      • Kiyatkin E.A.
      Brain temperature homeostasis: physiological fluctuations and pathological shifts.
      ). Hepatic and renal insult may occur also as a consequence of secondary hypoperfusion as the sympathetic nervous system shunts blood flow to the skin to facilitate heat release (
      • Atha W.F.
      Heat-related illness.
      ). Cytokine-mediated systemic inflammatory responses and disseminated intravascular coagulation may lead to multiorgan failure and mortality (
      • Atha W.F.
      Heat-related illness.
      ,
      • Jardine D.S.
      Heat illness and heat stroke.
      ).
      Computed tomography (CT) of the brain in acute heat stroke is usually normal (
      • Albukrek D.
      • Bakon M.
      • Moran D.S.
      • et al.
      Heat-stroke-induced cerebellar atrophy: clinical course, CT and MRI findings.
      ). Magnetic resonance imaging (MRI) abnormalities are characteristically symmetric and include lesions hyperintense on FLAIR and DWI sequences in the cerebellum, external capsule and adjacent lateral putamen, medial thalamus, and hippocampus (
      • Lee J.S.
      • Choi J.C.
      • Kang S.Y.
      • et al.
      Heat stroke: increased signal intensity in the bilateral cerebellar dentate nuclei and splenium on diffusion-weighted MR imaging.
      ). Patchy cortical lesions may also be seen (
      • Muccio C.F.
      • De Blasio E.
      • Venditto M.
      • et al.
      Heat-stroke in an epileptic patient treated by topiramate: follow-up by magnetic resonance imaging including diffusion-weighted imaging with apparent diffusion coefficient measure.
      ). Punctate hemorrhagic lesions have been described in the cerebellar hemispheres, brain stem, corona radiata, and frontal lobes on susceptibility-weighted images (
      • Li J.
      • Zhang X.Y.
      • Zou Z.M.
      • et al.
      Heat stroke: typical MRI and (1)H-MRS features.
      ,
      • Zhang X.-Y.
      • Li J.
      Susceptibility-weighted imaging in heat stroke.
      ,
      • Murcia-Gubianas C.
      • Valls-Masot L.
      • Rognoni-Amrein G.
      Brain magnetic resonance imaging in heat stroke.
      ). Diffusion tensor imaging has shown fractional anisotropy of cerebellar white and gray matter (
      • Li J.
      • Zhang X.Y.
      • Wang B.
      • et al.
      Diffusion tensor imaging of the cerebellum in patients after heat stroke.
      ).
      Postmortem studies of heat stroke have demonstrated severe loss of cerebellar Purkinje cells and degeneration of Purkinje cell axons with myelin pallor of the white matter of the cerebellar folia and of the hilum of the dentate nuclei. Brain areas such as Ammon's horn that are typically vulnerable to hypoxia were spared (
      • Bazille C.
      • Megarbane B.
      • Bensimhon D.
      • et al.
      Brain damage after heat stroke.
      ).

      6.1 Causes of hyperthermia

      Heat-related illness may be divided into passively and actively induced mechanisms (Table 5). Classical heat stroke occurs in individuals who have impaired thermoregulatory physiology and are deficient in the mechanisms for heat dissipation or lack the awareness or the means to escape from a hot environment (
      • Santelli J.
      • Sullivan J.M.
      • Czarnik A.
      • Bedolla J.
      Heat illness in the emergency department: keeping your cool.
      ,
      • Clark W.G.
      • Lipton J.M.
      Drug-related heatstroke.
      ,
      • Anderson R.J.
      • Reed G.
      • Knochel J.
      ,
      • Hart G.R.
      • Anderson R.J.
      • Crumpler C.P.
      • et al.
      Epidemic classical heat stroke: clinical characteristics and course of 28 patients.
      ,
      • Centers for Disease Control
      Heatstroke—United States, 1980.
      ). A paradoxical feature is that the skin may appear red, hot, and dry, as patients with classical heat stroke are often anhidrotic (
      • Clark W.G.
      • Lipton J.M.
      Drug-related heatstroke.
      ). The absence of sweating in a heat-stressed individual should not be interpreted as evidence against hyperthermia.
      Table 5Clinical features of classical versus exertional heat stroke.
      ClassicalExertional
      CircumstancesOften in epidemics during summer heat waves, occurs without preceding physical activityAthletic activity or strenuous exertion during variably warm or hot weather or while wearing heat-retaining clothing
      AgeChildren and elderlyAdults young to middle age
      HealthIllness or medication impairing thermoregulatory sweatingHealthy
      SweatingOften reduced or absentMay be present
      Acid base disturbanceRespiratory alkalosisLactic acidosis
      Acute renal failureRarelyFrequently
      RhabdomyolysisRarelyFrequently
      Disseminated intravascular coagulationRarelyFrequently
      Exertional heat stroke, by contrast, typically occurs in healthy young individuals who engage in strenuous physical exercise during hot weather or in environments that restrict heat dissipation (
      • Clark W.G.
      • Lipton J.M.
      Drug-related heatstroke.
      ,
      • Anderson R.J.
      • Reed G.
      • Knochel J.
      ). Sweating is an inadequate indicator of the degree of heat stress, but the cessation of sweating in exertional heat stroke may be an ominous sign (
      • Clark W.G.
      • Lipton J.M.
      Drug-related heatstroke.
      ). The estimated 9000 high school athletes are treated for heat-related illness each year in the U.S. (
      • Kerr Z.Y.
      • Casa D.J.
      • Marshall S.W.
      • Comstock R.D.
      Epidemiology of heat illness among U.S. high school athletes.
      ). Exertional heat stroke is, in fact, one of the leading causes of preventable nontraumatic injury as well as a recognized cause of sudden death during sport (
      • Casa D.J.
      • DeMartini J.K.
      • Bergeron M.F.
      • et al.
      National Athletic Trainers' Association position statement: exertional heat illnesses.
      ,
      • Casa D.J.
      • Armstrong L.E.
      • Ganio M.S.
      • Yeargin S.W.
      Exertional heat stroke in competitive athletes.