Sage Journals: Discover world-class research

Abstract

Heatstroke is the most severe form of heat-related disorders that include mild heat intolerance, heat exhaustion and heat stress. The incidence of heat-related disorders is increasing due to several factors that include climate change, co-morbidities and drug usage. Patients with heatstroke present with a core body temperature above 40°C, multiorgan dysfunction and central nervous system disorder. The pathogenesis of heatstroke is not fully understood; however, heat-shock proteins, inflammatory cytokines and their modulators have been implicated. The clinical biochemistry laboratory plays an important role in the management of patients with heatstroke. Biochemical findings in patients with heatstroke include elevated urea, creatinine, cardiac and skeletal muscle enzymes, myoglobin and troponin. There is also biochemical evidence of metabolic acidosis, respiratory alkalosis, hepatic injury with elevated enzyme levels as well as abnormal hematological and coagulation indices. This review article aims at increasing awareness of the biochemical changes seen in patients with heatstroke and their possible role in prognosis and in elucidating the pathogenesis of heatstroke.

Introduction

Scope

This review article, aimed at increasing awareness of heat-related disorders, reviews the theories and experimental evidence for the pathophysiology of heat-related disorders. The review discusses biochemical findings in patients with heatstroke and their prognostic and diagnostic values, the clinical utility of markers of inflammation, and recent advances in therapy as well as discussion on future studies.

Heat-related illness has been known for a long time. For instance, in Amara, Iraq, on July 15 1916, with a temperature above 43°C in the shade, Sir Victor Horsely, the pioneer neurosurgeon turned neuropathologist, had walked several miles in the sun to visit a sick officer; Dr Horsely returned to camp complaining of headache. He developed a fever of 40°C and was admitted to the military hospital. His temperature continued to escalate and he lapsed into coma and died a day later at the age of 59. The cause of death was recorded as heatstroke.¹

Climate change

The incidence of heat-related disorders such as heat exhaustion and heatstroke are increasing due to many factors including climate change.² In recent years, a significant number of deaths both in Europe^3–5 and in the USA^2,6 have been attributed to heatstroke.

In 2003, Central Europe experienced the hottest summer since year 1500 with average temperatures being 3.5°C above normal.³ Heat-related deaths were estimated to be between 22,000 and 45,000 persons over a two-week period.⁴ The same heat wave caused an estimated 14,800 deaths in France^5,7 alone causing an excess mortality of 54%, which correlated with increased day and night ambient temperature.⁸ Most frequent causes of death were reported to be dehydration and hyperthermia followed by disorders of the cardiovascular system. Death due to heatstroke was also seen among hospitalized patients in France; 19% of all hospital deaths during the heat wave were attributed to heatstroke.^9,10

An increase of 7% in mortality was observed during the same period in Switzerland¹¹ and was heat wave related. Excess mortalities have also been reported for a number of other European countries.^12–15

Heat mortality is shown to follow a J-shaped function with a steeper slope at higher temperatures with a variable minimum of 26–28°C.¹⁶ Earlier studies from North America have shown that preventive measures such as meteorological forecasts (heat advisories 1–3 days prior to reaching severe heat levels) to initiate public health intervention and response have reduced heat-related mortality.^10,17,18

An Intergovernmental Panel on Climate Change projects a global average warming of 0.6–2.5°C in the next 50 years and 1.4–8.5°C by the year 2100, thus presenting serious medical and social problems. This wide range is a reflection of the assumptions about future trends in greenhouse gas emissions.⁷ There is also a link between global warming and the occurrence of regional heat waves. Heat waves affecting a number of countries have raised worldwide concern about heat-related illness.

Physiology

Body heat is acquired from both the environment and from metabolic reactions where, for instance, 60–70 kcal causes an increase of 0.8°C in body temperature per hour.¹⁹ The process of thermoregulation, however, ensures that the human body's core temperature is closely maintained at 37°C. Temperature receptors in the skin and viscera transmit information to temperature-sensitive neurons in the anterior and ventromedial hypothalamus,^20,21 preoptic areas and in the mid-brain, brain stem and spinal cord. Increased body temperature results in increased firing of these neurons, and similarly cooling reduces their firing rate.²¹ Responses to hyperthermia include increased blood flow from the visceral to peripheral areas to allow for heat loss by convection, behavioural changes such as moving to a cool area, and increased sweating facilitating heat loss by evaporation. It has been estimated that 1 kcal is dissipated by 1.7 mL of sweat;²² this is, however, influenced by both ambient temperature and humidity. Heat-related illness can occur when high ambient temperature exceeds the ability of the body to dissipate heat. This is exacerbated by high humidity, which reduces the body's capacity to dissipate heat.

Heat-related illness represents a continuum: the mildest form is heat intolerance, followed by heat stress, characterized by symptoms of discomfort following exposure to a hot environment. In the absence of adequate hydration, the patient may progress to heat exhaustion, characterized by generalized weakness, thirst, syncope and cardiovascular dysfunction; this may progress to the most severe form, heatstroke, depending on the patient's thermoregulatory mechanisms.

Heatstroke is a life-threatening disorder attributed to complete loss of thermoregulation. It is characterized by a core body temperature above 40°C, multiorgan dysfunction and central nervous system dysfunction ranging from delirium, convulsions, loss of consciousness or coma, and death.²³ The multiorgan dysfunction includes renal, musculoskeletal, cerebrovascular, cardiovascular and hepatic as well as cerebral disorders. The presence of adequate sweat is essential for heat dissipation. Dehydration due to reduced fluid intake will impair sweating, and thus potentiate heat-related illness. Lack of sweating and presence of hot dry skin on presentation is the hallmark of heatstroke due to impaired heat dissipation compared with that of exertional hyperthermia.²⁴ Hypovolemia is a common finding among patients with heatstroke with increased blood viscosity and a tendency for thrombosis.²⁵ This may progress to disseminated intravascular coagulation (DIC), which has been reported in 45% of patients.²⁶ Furthermore, autopsy of patients with heatstroke shows evidence of haemorrhage, necrosis and microthrombi in several organs indicating DIC.²⁷

The incidence of heatstroke is variable and is probably underestimated, ranging from 17.6 to 250 cases/100,000 population, depending on seasonal and geographical distribution.^28,29 However, there has recently been a marked increase thought to be associated in part with increased ambient temperature. Heat-related mortality rate is high and ranges between 33% and 80% where terminal events include shock, arrhythmias, myocardial infarction, renal failure and various neurological dysfunctions.^30,31 Residual neurological dysfunction was experienced by 17% of survivors.³²

The elderly and children, sedentary individuals, women, workmen, sportsmen and soldiers are at increased risk of dehydration and reduced heat dissipation and therefore heat-related illness.^33,34 Infants and children have reduced body surface area, which reduces heat dissipation compared with adults. This is in addition to their lower sweating rate. The elderly, in addition to being on many medications, have reduced response to heat. Obesity is also a contributing factor.³⁵

The biochemical changes seen in patients with heatstroke are of great interest in unravelling the pathogenesis of heatstroke and in the prognosis and monitoring of response to therapy in these patients. It is noteworthy that some of the observed changes are similar to those seen in patients with sepsis with involvement of inflammatory mediators and cytokines.

Pathogenesis

Although the pathogenesis of heatstroke is not fully understood, a number of mechanisms have been described based on correlation studies of patients with heatstroke^36–39 and animal model studies.^40–44 With few exceptions, experimental evidence from animal studies was obtained following exposure to direct heat using heat chambers and water baths rather than from exertional studies, which is the case in most heatstroke patients.

In vitro studies showed that direct heat (hyperthermia) per se accelerates enzymatic reaction rates, which may lead to imbalance of multistep metabolic processes. If markedly elevated, heat causes protein denaturation and loss of activity, loss of membrane integrity and ultimate cell death.⁴⁵ The temperature associated with heatstroke ranges between 41 and 42°C,⁴⁰ but temperatures as high as 47°C have been reported.³⁶ Critical thermal maximum, the minimum core-body temperature that is lethal to an organism, is variable, making it difficult to predict thermal injury. Many factors may enhance the risk of heatstroke e.g. underlying cerebrovascular dysfunction, concurrent illness such as infections, and drug therapy.

Cytokines

Cytokines play a role in heat production and have been implicated in the pathogenesis of heatstroke. Studies in patients with heatstroke^36–39 and experimental animal studies^40–44 showed markedly elevated interleukin-6 (IL-6), interleukin-1 (IL-1) and tumour necrosis factor-α (TNF-α) concentrations. IL-1 and TNF-α stimulate the release of IL-6 from activated lymphocytes, macrophages and fibroblasts.⁴⁶ IL-6 in turn stimulates hepatic synthesis and release of C-reactive protein (CRP).⁴⁷ The activities of TNF-α and IL-1 are attenuated by circulating inhibitors namely TNF-soluble receptors (TNF-sr) I and II^48,49 and IL-1 receptor antagonist (IL-1ra), respectively.⁵⁰ It is hypothesized that these cytokine inhibitors, by inhibiting cytokine activity, afford a protective mechanism against a continued inflammatory process.

Hashim et al. and others^36–38 have reported elevated pro-inflammatory cytokines, namely, IL-1 α, IL-1-β, IL-6, IL-10 and TNF-α as well as their associated proteins, IL-1-ra, IL-6-sr, and TNF-α-srs in patients with heatstroke.

Elevated levels of pro-inflammatory cytokines and their associated proteins seen on admission eventually declined following therapeutic volume repletion and body cooling. Although IL-6 concentrations at admission were not significantly different between survivors and non-survivors,³⁶ differences became significant at >6 h following admission. Interestingly, the extent of cytokine response correlated with outcome, where sustained high concentrations despite body cooling were associated with poor outcome. The lack of correlation at admission may be a consequence of variable presentation times. Furthermore, the lack of correlation between IL-6 concentrations and core body temperature at admission suggest a diminished role for IL-6 in modulating core body temperature. This finding is in contrast to that from animal studies, where IL-6 was thought to play a role in heat dissipation where concentrations correlated with recovery from heatstroke;⁴⁰ IL-6 knockout mice had difficulty dissipating heat and as a consequence, increased mortality when compared with wild type.^40–42 This suggests a protective role for IL-6 which is in contrast to data obtained from correlation studies.^36,38 Furthermore, experimental hyperthermia is characterized by three phases (tri-phasic hyperthermic curve),⁴¹ i.e. (1) An initial rapid increase in core body temperature, followed by (2) an equilibrium plateau, then (3) a rapid increase in core temperature due to breakdown of thermoregulatory mechanisms. In animal models, a hypothermic phase is observed during the recovery phase from heatstroke. The duration and depth of this phase is directly related to heat severity.⁴² IL-6 is elevated at this phase and the extent of elevation correlates with survival.⁴⁰ This hypothermic phase was not observed in correlation studies in patients with heatstroke; it is possible that treatment modalities masked the hypothermic phase.

Experimental evidence has shown that at elevated temperatures, there is increased expression of pro-inflammatory cytokines, i.e. IL-1, IL-6, IL-2, TNF-α, granulocyte and macrophage colony-stimulating factor and interferon which supports a role for the cytokines in the pathophysiological response to heatstroke.^51–53 In heat stress experiments in experimental mouse models, however, IL-1β was elevated at initiation of heat stress. IL-6 did not rise significantly until the hyperthermic phase and remained elevated at 24 h of recovery.^42,43

Although it has been shown that high IL-6 levels correlate with heatstroke morbidity and mortality,^36,37 evidence for what would be an expected protective effect of neutralizing IL-6 is not available.

Elevated cytokine modulators, i.e. TNF-sr-II levels, have been observed in various pathological conditions including endotoxemia and infection and several reports have shown correlation between concentrations of TNF and its soluble receptor.^54–56 These findings support the notion that sepsis and endotoxemia are similar in their cytokine response seen in heatstroke.

Furthermore, production of glucocorticoids by the hypothalamic–pituitary–adrenal axis is shown to inhibit IL-1 release at both the expression and the post-translational level.^57–60

In summary, evidence from human studies and from animal models indicates that pro-inflammatory cytokines and their associated modulators play a role in the pathogenesis of heatstroke. Although those cytokines are significantly elevated during heatstroke, correlation with body temperature as well as outcome is varied.

Heat shock proteins

Heat shock proteins (HSPs) were initially identified as being produced in response to hyperthermia. However, they are synthesized in response to many other stimuli such as ischaemia, inflammation, exposure to oxidants, to heavy metals and to radiation.^61–66 They are produced by many tissues and are classified according to their molecular weight ranging from 10 to >90 kDa.⁶⁴

HSPs are described as molecular chaperones because of their action in preventing abnormal folding of cellular proteins during biosynthesis and in restoring unfolded, misfolded and denatured proteins.⁶² In doing so they help to maintain protein structure and function, to protect against oxidative and heat damage, and to maintain correct antigen presentation and therefore an appropriate immune response. Circulating concentrations of HSPs as well as antibodies directed against them have been reported in the serum of healthy individuals and from patients with heatstroke.^67,68

Synthesis of the most studied HSP 72 can be stimulated by hypoxia,^69,70 ischaemia,⁷¹ acidosis,⁷² energy depletion,⁷³ immune responses⁷⁴ and ultraviolet radiation.⁶⁶ Higher concentrations of circulating HSP 72 were found in subjects working at high temperatures compared with those working at normal temperature,⁷⁵ suggesting that it might be involved in response to heat stress. Furthermore, elevated concentrations were detected among healthy subjects when their temperature was greater than 39°C, compared with lower concentrations among patients who had heatstroke,⁷⁶ thus suggesting a protective role for HSP.

Over-expression of HSP 72 in heart and brain tissue from transgenic mouse studies was associated with attenuated circulatory shock and cerebral ischaemic injury in an in vivo model of heatstroke, and, thus afforded protection.⁷⁷ These findings indicate a causal relationship between the over-expression of HSP 72 in multiple vital organs and protection from heatstroke.

Auto-antibodies (IgG, IgM, IgA) to HSPs have been detected in patients with auto-immune disorders such as rheumatoid arthritis (anti-HSP 65)⁷⁸ and systemic lupus erythromatosis (SLE) (anti-HSP 70 in 85% of patients with SLE).⁷⁹

The incidence of antibodies to HSP 70 in patients with severe heatstroke is significantly higher (57%) compared with those with mild heatstroke and no heat-related illness.⁷⁶ It is possible that the presence of antibodies neutralizes HSP 70 and, thus limits its protective role in patients with heatstroke. Measuring the titre of HSP 70 antibodies could be used to identify those at risk of heatstroke.⁶⁸ It is important to note that there is an age-specific auto-antibodies response, which may explain the increased incidence of severity of heatstroke among the elderly.

Thermo-tolerance and acclimatization

Differences in patient response to heat stress and in survival rates suggest that adaptation and thermo-tolerance may be involved. For instance, heatstroke is accompanied by arterial hypotension, reduced cerebral blood flow (both of which lead to ischaemia with cellular damage) and reduced survival rate. Development of thermo-tolerance, however, is associated with maintained arterial pressure as well as adequate cerebral blood flow.

Acclimatization is adaptation to hot climate. This is achieved following improved cardiovascular function, increased glomerular filtration rate, salt conservation, activation of the renin aldosterone axis, and conservation by sweat glands and the kidneys, which results in expansion of plasma volume. In severe heat stress, a normal response would be an increase in cardiac output by up to 20 L/min. Inability to increase cardiac output due to cardiovascular disease or salt depletion and hypovolemia, or medication that impairs cardiac function would increase susceptibility to heatstroke.

Evidence from human studies as well as from animal models shows elevated HSPs during heatstroke. Human subjects and animal models with elevated HSPs show favourable outcomes compared with those models with circulating anti-HSPs antibodies (Table 1). In several animal experiments, induced over-expression of HSP 70-72 showed an attenuated inflammatory cytokines (IL-1 and TNF-α) response following subsequent heatstroke.⁸⁷ In an in vivo model of heatstroke, HSP 72 is reported to reduce oxidative stress and energy depletion, so protecting against circulatory shock and cerebral ischaemia.⁷¹ Patients with high circulating anti-HSP antibodies had severe heatstroke compared with patients with low concentrations.⁷⁶

Table 1

Biochemical markers and their role in heatstroke

Biochemical factor	Role	References
Myoglobin	Renal impairment, rhabdomyolysis, myopathy	⁸⁰
AST, ALT	Liver dysfunction and injury	⁸⁰
LDH, CK, AST	Myopathy. Has prognostic value	⁸⁰
Na, K, urea, creatinine	Assesses hydration status, renal function	⁸¹
Blood gases	Metabolic acidosis and respiratory alkalosis	⁸²
Lactate/pyruvate	Assesses degree of ischaemia	^23,83
Glycerol (cerebral)	Extent of cerebral tissue damage	^23,83
Glutamate	Measure of ischaemic brain injury	^23,83
IL-6, TNF-α, IL-1	Pathogenesis of heatstroke. Concentrations correlate with outcome	^{36,38,39–44}
Procalcitonin	Limited prognostic value	^84–86
TNF-α-srII, IL-1 ra	Anti-inflammatory. Concentrations correlate with outcome	^36,54,55
Heat shock proteins	Protects against heatstroke-induced circulator shock. Reduces oxidative stress, cerebral ischaemia and energy depletion. Attenuates inflammatory cytokines IL-1 and TNF-α	⁶⁸
HSPs antibodies	Prognostic value	⁶⁸

AST, aspartate transaminase; ALT, alanine transaminase; LDH, lactate dehydrogenase; CK, creatine kinase; IL-6, interleukin-6; TNF-α, tumour necrosis factor-α; IL-1, interleukin-1; TNF-α-srII, tumour necrosis factor-α-soluble receptor II; IL-1ra, interleukin-1 receptor antagonist; HSPs, heat shock proteins

Although the precise mechanisms for the improvement in heat tolerance associated with HSP overproduction is unclear, this may be associated with protection of proteins against direct heat damage by preventing protein denaturation or by re-folding misfolded proteins.⁸⁸

Biochemical findings associated with heatstroke

Biochemical parameters measured in patients presenting to the emergency department and suspected of heatstroke usually include blood electrolytes (Na and K), urea, creatinine, creatine kinase (CK), aspartate transaminase (AST), alanine transaminase (ALT), lactate, arterial blood gases as well as haematological parameters. In practice, they are mainly used to evaluate hydration status, electrolyte imbalance, end organ damage as well as support the clinical management of heat-related disorders. It is worth noting that heatstroke patients are hypovolemic and adequate blood sample volume may be difficult to obtain.

Biochemical abnormalities seen in patients with heatstroke are initially hypokalaemia, thought to be due to either increase uptake by muscles due to catecholamine-stimulated Na-K ATPase, increased blood flow to muscles and or to intracellular acidosis. This is followed by hyperkalemia attributed to heatstroke-associated rhabdomyolysis and cellular leakage.⁸¹ Furthermore, increased glucose utilization results in hypophosphataemia, which might be masked by hyperphosphataemia due to cellular leakage and ensuing renal impairment.⁸⁹

Acid–base status

Patients with heatstroke present with mixed acid–base disturbance. The predominant findings on admission are those of metabolic acidosis followed by respiratory alkalosis.⁸² Hypovolemia and poor muscle perfusion seen in patients with heatstroke results in lactic acidosis. Furthermore, the higher the body temperature is, the greater the likelihood of acidosis. There is a compensatory respiratory alkalosis.

Renal function tests

Urea and creatinine will be elevated due to intrinsic renal injury, e.g. following deposition of myoglobin due to rhabdomyolysis. Increased plasma creatinine is probably due to reduced renal blood flow and glomerular filtration rate as well as to the release of creatine from muscle. Elevated urea may be due to prerenal causes such as hypovolaemia, cardiac failure and/or to intravascular haemolysis. Elevated circulating CK activity suggests development of rhabdomyolysis. Although not widely available, measurement of serum and urine myogloblin may help elucidate this cause of renal failure.

Other laboratory findings associated with kidney function include urine hyperosomolality due to dehydration, proteinuria due to muscle damage, haematuria, myoglobinuria and renal tubular casts.

Metabolism of increased purines released from damaged cells to uric acid results in hyperuricaemia, which is potentiated by decreased renal excretion and ensuing lactic acidosis.

Cardiac and skeletal muscle markers

Elevated CK, AST and lactate dehydrogenase (LDH) are frequently seen in patients with heatstroke. This indicates skeletal and cardiac muscle injury. Furthermore, elevated LDH, AST and CK at admission were reported to be associated with poor outcome in patients with heatstroke and are probably of skeletal origin.⁸⁰ Elevated troponin I concentrations have also been reported in exertional heatstroke.⁹⁰

Liver injury and dysfunction tests

Circulating activities of liver enzymes (AST, ALT, alkaline phosphatase and γ-glutamyl transferase) are variable in patients with heatstroke. For instance 75% of patients with heatstroke have serum ALT activity within normal limits.³⁶ Interestingly, median activity levels were higher among non-survivors compared with survivors.³⁶ AST and LDH enzymes are significantly elevated among patients with heatstroke and are associated with worse outcome.⁸⁴

Haematological findings are those of leukocytosis due to inflammatory processes, prolonged international normalized ratio (INR) and activated partial thromboplastin time (aPTT), fibrinolysis, positive D-dimer, thrombocytopenia associated with coagulopathy and DIC.⁹¹

C-reactive protein

Acute phase reactants: CRP is synthesized by hepatocytes in response to cytokines, mainly IL-6. It is a positive acute-phase reactant and elevated concentrations are seen in patients with inflammation, sepsis and trauma.⁴⁷ Concentrations start to rise within 6–8 h reaching a peak at 48–72 h. Hashim et al. ³⁶ and others³⁷ have shown that CRP is markedly elevated in patients with heatstroke and remains so despite cooling. Furthermore, concentrations peaked at 48 h and correlated with outcome. IL-6 has been implicated in the pathogenesis of heatstroke as described earlier; it is becoming increasingly available in automated immunoanalysers, and its measurement has been mainly used in the investigation of sepsis, premature rupture of membranes,⁹² patients at risk of acute coronary syndrome and in following the systemic inflammatory response.⁹³

Procalcitonin

Procalcitonin is a precursor peptide of calcitonin. It is produced by the parafollicular (c) cells distributed throughout the thyroid gland and has been shown to be elevated in patients with several systemic inflammatory conditions.^85,86 In patients with heatstroke, elevated procalcitonin concentrations at admission and subsequent increase reaching a plateau over a 24-h period were associated with survival whereas low concentrations were associated with poor outcome.⁸⁴

Metabolic markers

Although not widely measured, other biochemical markers of interest include cerebrospinal fluid (CSF) lactate, pyruvate and glycerol. In patients with heatstroke, decreased blood flow and thus reduced cerebral partial pressure of oxygen causes brain ischaemia evident by increased CSF lactate to pyruvate ratio. Elevated glycerol concentrations indicate ongoing tissue damage. In animal studies, cerebral glycerol, glutamate and lactate to pyruvate ratio is significantly elevated in rats with heatstroke compared with normal controls.⁸³

Therapeutic measures

Rapid cooling of the body's core temperature is the principal treatment modality. Reduction of core temperature to <38.9°C within 30 min achieves optimal survival and reduced end-organ damage.⁹⁴ Several cooling methods have been described. They include spraying water over the patient and facilitating evaporation by air flow (operative cooling), immersing the entire body or part of the body (hands) in ice-cool water. A few reports indicated a value for iced gastric, bladder or peritoneal lavage.⁹⁵ Patients are often given dantrolene to limit heat generated by muscle hyperactivity even in patients with heatstroke; this accelerates cooling attempts. Dantrolene is a muscle relaxant that attenuates the amount of calcium released from the sarcoplasmic reticulum of skeletal muscle to the cytosol inhibiting calcium-dependent muscle contraction.⁹⁶

Therapeutic intervention is used to prevent and treat end-organ damage, e.g. to restore renal function, to correct coagulopathy, blood gas abnormalities, hypoxemia, acidosis and alkalosis as well as electrolyte disturbances. Biochemical measurement of electrolytes, urea and creatinine help monitor response to therapy.

Drugs

Drug-induced hyperthermia is widely recognized.⁹⁷ For instance, drugs affecting the concentrations of the hypothalamic neurotansmitters, dopamine, nor-adrenaline and serotonin, which are known to play a role in the hypothalamic control of body temperature, will influence heat regulation. Thyroid hormones play a role in thermogenesis and drugs affecting thyroid function influence heat regulation.⁹⁸ Similarly, drugs that cause or interfere with vasoconstriction, sweating and shivering will also have an effect on thermogenesis.

Drugs of abuse inducing hyperthermia are well recognized.^97,99 They include Ecstasy (3, 4 methylene-dioxymethamphetamine [MDMA, the Rave drug]), amphetamines, methamphetamines and cocaine. Patients present with what is termed serotonin syndrome (due to increased serotonin concentrations); in addition to marked hyperthermia (>43.9°C) in approximately one-third of patients, they exhibit diaphoresis, tachycardia, muscle rigidity, rhabdomyolysis, seizures, hyperkalemia and metabolic acidosis.¹⁰⁰ In serotonin syndrome due to the drug Ecstasy, fatality is about 67% and correlates directly with core body temperature. It occurs within two hours of drug intake with 25% of patients presenting at more than 24 h. MDMA is consumed and then usually followed by vigorous exercise such as dancing. The drug increases the body's temperature, which is aggravated by vigorous exercise and the frequently hot, humid and overcrowded dance clubs. Ecstasy is frequently adulterated with a cough suppressant (dextromethorphan), which causes dehydration and prevents adequate sweating. Other drugs associated with exertional heatstroke are ephedrine containing medications; although the mechanism is not known, it is suggested that the drug may produce heat or impair heat dissipation following vasoconstriction.

Patients (1:5000–100,000) exposed to volatile anaesthetic gases, halothane, sevoflurane, desflurane and succinyl choline will show signs of hyperthermia as part of a syndrome known as malignant hyperthermia.¹⁰¹ Anaesthetic agents inhibit mitochondrial ATP synthesis, which will result in uncoupling and release of the built up electrochemical energy in the mitochondrial inner membrane into passive transfer to heat energy. Uncoupling proteins (UPC-1 and 3) have been shown to facilitate passive flow of electrons across the mitochondrial membrane.⁹⁹ The uncoupling reaction is enhanced by drugs such as norepinephine and β-3 adrenoreceptor agonists.

Future studies

Correlation and animal studies suggest a role for cytokines and HSPs in the pathogenesis of heatstroke. Cooling therapy is the only validated therapy for heatstroke. Mortality remains high and a high percentage of survivors have neurological deficit. Studies to further elucidate the pathogenesis as well as therapeutic modulation of the cytokine response are urgently required.

Conclusion

The incidence of heat-related illness is increasing, and heatstroke is the most severe form associated with mortality and morbidity. Although the pathogenesis of heatstroke is not fully understood, inflammatory cytokines and their associated proteins as well as HSPs play a significant role in both mediating the response, in heat tolerance, and in prognosis. Early recognition combined with therapeutic intervention improves survival and outcome.

DECLARATIONS

Conflicts of interest: None.

Funding: None.

Ethical approval: None. Not applicable. No patient data were reviewed. Review article.

Guarantor: IAH.

Contributorship: IAH is the sole author.

References

Tan

, Black

. Sir Victor Horsley (1857–1916): pioneer of neurological surgery. Neurosurgery 2002;50:607–11

Luber

, Sanchez

, Conklin

. Heat-related deaths – United States, 1999–2003. MMWR Morb Mortal Wkly Rep 2006;55:796–8

Luterbacher

, Dietrich

, Xoplaki

, Grosjean

, Wanner

. European seasonal and annual temperature variability, trends, and extremes since 1500. Microb Ecol 2004;303:1499–503

International Federation of Red Cross and Red Cresent Societies. World Disaster Report. 2004

Pirard

, Vandentorren

, Pascal

, Summary of the mortality impact assessment of the 2003 heat wave in France. Euro Surveill 2005;10:153–6

Haines

, Kovats

, Campbell-Lendrum

, Corvalan

. Climate change and human health: impacts, vulnerability, and mitigation. Lancet 2006;367:2101–9

Meehl

, Stocker

, Collins

, Global climate projections. In: Solomon

, Qin

, Manning

, Chen

, , eds. Climate Change 2007: The Physical Science Basis Contribution of Working Group I to the Fourth Assessment Report of the INtergovernmental Panel on Climate Change. Cambridge, UK and New York, NY, USA: Cambridge University Press, 2007

Vandentorren

, Suzan

, Medina

, Mortality in 13 French cities during the August 2003 heat wave. Am J Public Health 2004;94:1518–20

Ferron

, Trewick

, Le Conte

, [Heat stroke in hospital patients during the summer 2003 heat wave: a nosocomial disease]. Presse Med 2006;35:196–9

10.

Koppe

, Kovats

, Jendritzky

, Menne

. Heat-waves: Risks and Responses. Copenhagen: World Health Organization, 2004

11.

Grize

, Huss

, Thommen

, Schindler

, Braun-Farhlander

. Heat wave 2003 and mortality in Switzerland. Swiss Med Wkly 2003;105:200–5

12.

Michelozzi

, de' Donato

, Accetta

, Impact of heat waves on mortality-Rome, Italy, June–August 2003. MMWR Morb Mortal Wkly Rep 2004;53:369–71

13.

Martinez Navarro

, Simon Soria

, Lopez-Abente

. Evaluation of the impact of the heat wave in the summer of 2003 on mortality. Gac Sanit 2004;18(Suppl 1):205–58

14.

Fisher

, Brunekreef

, Lebret

. Air pollution related deaths during the 2003 heatwave in the Netherlands. Atmos Environ 2004;38:1083–5

15.

Stedman

. The predicted number of air pollution related deaths in the UK during the August 2003 heatwave. Atmos Environ 2003;38:1087–90

16.

McMichael

, Haines

, Slooff

, Kovats

. Climate Change and Human Health. An Assessment by a Task Group on Behalf of the World Health Organization, the World Meteorological Organization and the United Nations Environment Programme. Geneva: World Health Organization, 1996

17.

Weisskopf

, Anderson

, Foldy

Heat wave morbidity and mortality, Milwaukee, Wis, 1999 vs 1995: an improved response?

Am J Public Health 2002;92:830–3

18.

Smoyer

. A comparative analysis of heat waves and associated mortality in St. Louis, Missouri – 1980 and 1995. Int J Biometerol 1998;42:44–50

19.

Passmore

, Durnin

. Human energy expenditure. Physiol Rev 1955;35:801–40

20.

Boulant

. Cellular mechanisms of temperature sensitivity in hypothalamic neurons. Prog Brain Res 1998;115:3–8

21.

Hori

, Katafuchi

. Cell biology and the functions of thermosensitive neurons in the brain. Prog Brain Res 1998;115:9–23

22.

Adams

, Fox

, Fry

, MacDonald

. Thermoregulation during marathon running in cool, moderate, and hot environments. J Appl Physiol 1975;38:1030–7

23.

Sucholeiki

. Heatstroke. Semin Neurol 2005;25:307–14

24.

Knochel

. Exertional heat stroke: pathophysiology of heat stroke. In: Hopkins

, Ellis

, eds. Hyperthermic and Hypermatabolic Disorders. Cambridge: Cambridge University Press, 1996:42–62

25.

Keatinge

, Coleshaw

, Easton

, Increased platelet and red cell counts, blood viscosity, and plasma cholesterol levels during heat stress, and mortality from coronary and cerebral thrombosis. Am J Med 1986;81:795–800

26.

Dematte

, O'Mara

, Buescher

, Near-fatal heat stroke during the 1995 heat wave in Chicago. Ann Intern Med 1998;129:173–81

27.

Chao

, Sinniah

, Pakiam

. Acute heatstroke deaths. Pathology 1981;13:145–56

28.

Ghaznawi

, Ibrahim

. Heat stroke and heat exhaustion in pilgrims performing the Hajj (annual pilgrimage) in Saudi Arabia. Ann Saudi Med 1987;7:323–6

29.

Jones

, Liang

, Kilbourne

, Morbidity and mortality associated with the July 1980 heat wave in St Louis and Kansas City, Mo. JAMA 1982;247:3327–31

30.

Vicario

, Okabajue

, Haltom

. Rapid cooling in classic heatstroke: effect on mortality rates. Am J Emerg Med 1986;4:394–8

31.

Seraj

. Heat stroke during Hajj (Pilgrimage) – an update. Middle East J Anesthesiol 1992;11:407–41

32.

Hart

, Anderson

, Crumpler

, Epidemic classical heat stroke: clinical characteristics and course of 28 patients. Medicine (Baltimore) 1982;61:189–97

33.

Lugo-Amador

, Rothenhaus

, Moyer

. Heat-related illness. Emerg Med Clin North Am 2004;22:315–27, viii

34.

Kilbourne

, Choi

, Jones

, Thacker

. Risk factors for heatstroke. A case-control study. JAMA 1982;247:3332–6

35.

Green

, Gilbert

, James

, Byard

. An analysis of factors contributing to a series of deaths caused by exposure to high environmental temperatures. Am J Forensic Med Pathol 2001;22:196–9

36.

Hashim

, Al-Zeer

, Al-Shohaib

, Al-Ahwal

, Shenkin

. Cytokine changes in patients with heatstroke during pilgrimage to Makkah. Mediators Inflamm 1997;6:1314–19

37.

Bouchama

, Al-Sedairy

, Siddiqui

, Shail

, Rezeig

. Elevated pyrogenic cytokines in heatstroke. Chest 1993;104:1498–502

38.

Hammami

, Bouchama

, Al-Sedairy

, Concentrations of soluble tumor necrosis factor and interleukin-6 receptors in heatstroke and heatstress. Crit Care Med 1997;25:1314–19

39.

, Wang

, Lin

, Chu

, Lin

. Role of circulating cytokines and chemokines in exertional heatstroke. Crit Care Med 2004;32:399–403

40.

Leon

. The thermoregulatory consequences of heat stroke: are cytokines involved? J Thermal Biol 2006;31:67–81

41.

Leon

, Blaha

, DuBose

. Time course of cytokine, corticosterone, and tissue injury responses in mice during heat strain recovery. J Appl Physiol 2006;100:1400–9

42.

Leon

. The use of gene knockout mice in thermoregulation studies. J Thermal Biol 2005;30:273–88

43.

Leon

, DuBose

, Mason

. Heat stress induces a biphasic thermoregulatory response in mice. Am J Physiol 2005;288:R197–204

44.

Lin

, Kao

, Su

, Hsu

. Interleukin-1 beta production during the onset of heat stroke in rabbits. Neurosci Lett 1994;174:17–20

45.

Goldstein

, Dewhirst

, Repacholi

, Kheifets

. Summary, conclusions and recommendations: adverse temperature levels in the human body. Int J Hyperthermia 2003;19:373–84

46.

Heinrich

, Castell

, Andus

. Interleukin-6 and the acute phase response. Biochem J 1990;265:621–36

47.

Hirano

, Akira

, Taga

, Kishimoto

. Biological and clinical aspects of interleukin 6. Immunol Today 1990;11:443–9

48.

Seckinger

, Isaaz

, Dayer

. Purification and biologic characterization of a specific tumor necrosis factor alpha inhibitor. J Biol Chem 1991;264:11966–73

49.

Chouaib

, Branellec

, Buurman

. More insights into the complex physiology of TNF. Immunol Today 1991;12:141–2

50.

Hannum

, Wilcox

, Arend

, Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 1990;343:336–40

51.

Dinarello

, Dempsey

, Allegretta

, Inhibitory effects of elevated temperature on human cytokine production and natural killer activity. Cancer Res 1986;46:6236–41

52.

Schmidt

, Abdulla

. Down-regulation of IL-1 beta biosynthesis by inducers of the heat-shock response. J Immunol 1988;141:2027–34

53.

Velasco

, Tarlow

, Olsen

, Temperature-dependent modulation of lipopolysaccharide-induced interleukin-1 beta and tumor necrosis factor alpha expression in cultured human astroglial cells by dexamethasone and indomethacin. J Clin Invest 1991;87:1674–80

54.

Van Zee

, Kohno

, Fischer

, Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo . Proc Natl Acad Sci US 1992;89:4845–9

55.

Andus

, Gross

, Holstege

, High concentrations of soluble tumor necrosis factor receptors in ascites. Hepatology 1992;16:749–55

56.

Spinas

, Keller

, Brockhaus

. Release of soluble receptors for tumor necrosis factor (TNF) in relation to circulating TNF during experimental endotoxinemia. J Clin Invest 1992;90:553–6

57.

Knudsen

, Dinarello

, Strom

. Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol 1987;139:4129–34

58.

Fenton

, Vermeulen

, Clark

, Webb

, Auron

. Human pro-IL-1 beta gene expression in monocytic cells is regulated by two distinct pathways. J Immunol 1988;140:2267–73

59.

Swolin-Eide

, Ohlsson

. Effects of cortisol on the expression of interleukin-6 and interleukin-1 beta in human osteoblast-like cells. J Endocrinol 1998;156:107–14

60.

Gewert

, Svensson

, Andersson

, Holst

, Sundler

. Dexamethasone differentially regulates cytokine transcription and translation in macrophages responding to bacteria or okadaic acid. Cell Signal 1999;11:665–70

61.

Christians

, Yan

, Benjamin

. Heat shock factor 1 and heat shock proteins: critical partners in protection against acute cell injury. Crit Care Med 2002;30:S43–50

62.

Saibil

. Chaperone machines in action. Curr Opin Struct Biol 2008;18:35–42

63.

Macario

, Conway de Macario

. Stress and molecular chaperones in disease. Int J Clin Lab Res 2000;30:49–66

64.

, Srivastava

. Heat-shock proteins. Curr Protoc Immunol 2004:Appendix 1:Appendix

65.

Kaufmann

. Heat shock proteins and the immune response. Immunol Today 1990;11:129–36

66.

Lindquist

. The heat-shock response. Annu Rev Biochem 1986;55:1151–91

67.

Pockley

, Shepherd

, Corton

. Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. Immunol Invest 1998;27:367–77

68.

Kim

. Diagnostic significance of antibodies to heat shock proteins. Clin Chim Acta 2003;337:1–10

69.

Hammerer-Lercher

, Mair

, Bonatti

, Hypoxia induces heat shock protein expression in human coronary artery bypass grafts. Cardiovasc Res 2001;50:115–24

70.

Schultz

, Arnold

. Heat shock (stress) proteins and autoimmunity in rheumatic diseases. Semin Arthritis Rheum 1993;22:357–74

71.

Wang

, Ke

, Lin

. Heat shock pretreatment may protect against heatstroke-induced circulatory shock and cerebral ischemia by reducing oxidative stress and energy depletion. Shock 2005;23:161–7

72.

Salt

, Inamura

, Thalmann

, Vora

. Calcium gradients in inner ear endolymph. Am J Otolaryngol 1989;10:371–5

73.

Ivanyi

, Ivanyi

. Elevated antibody levels to mycobacterial 65-kDa stress protein in patients with superficial candidiasis. J Infect Dis 1992;162:519–22

74.

Torigoe

, Tamura

, Sato

. Heat shock proteins and immunity: application of hyperthermia for immunomodulation. Int J Hyperthermia 2009;25:610–16

75.

, Pan

, Wu

T-C

, Pakiam

. Detection of heatshock protein by Western blot hybridization. Clin J Ind Hyg Occup Dis 1996;14:376–7

76.

Wang

, Wang

, Wu

, Autoantibody response to heat shock protein 70 in patients with heatstroke. Am J Med 2001;111:654–7

77.

Lee

, Wen

, Chang

, Chen

, Lin

. Heat shock protein 72 overexpression protects against hyperthermia, circulatory shock, and cerebral ischemia during heatstroke. J Appl Physiol 2006;100:2073–82

78.

Zlacka

, Vavrincova

, Hien Nguyen

, Hromadnikova

. Frequency of anti-hsp60, -65 and -70 antibodies in sera of patients with juvenile idiopathic arthritis. J Autoimmun 2006;27:81–8

79.

Arora

, Singh

, Sehgal

. Comparative evaluation of anti-heat shock protein antibodies in SLE and healthy controls. Scand J Rheumatol 1995;24:160–3

80.

Alzeer

, el-Hazmi

, Warsy

, Ansari

, Yrkendi

. Serum enzymes in heat stroke: prognostic implication. Clin Chem 1997;43:1182–7

81.

Akhtar

, al-Nozha

, al-Harthi

, Nouh

. Electrocardiographic abnormalities in patients with heat stroke. Chest 1993;104:411–14

82.

Bouchama

, De Vol

. Acid–base alterations in heatstroke. Intensive Care Med 2001;27:680–5

83.

Chang

, Chiu

, Chang

, Lin

. Effect of hypervolaemic haemodilution on cerebral glutamate, glycerol, lactate and free radicals in heatstroke rats. Clin Sci (Lond) 2004;106:501–9

84.

Nylen

, Al Arifi

, Becker

, Snider

Jr , Alzeer

. Effect of classic heatstroke on serum procalcitonin. Crit Care Med 1997;25:1362–5

85.

Sakr

, Sponholz

, Tuche

, Brunkhorst

, Reinhart

. The role of procalcitonin in febrile neutropenic patients: review of the literature. Infection 2008;36:396–407

86.

Hausfater

, Juillien

, Madonna-Py

, Serum procalcitonin measurement as diagnostic and prognostic marker in febrile adult patients presenting to the emergency department. Crit Care 2007;11:1–9

87.

Hung

, Chang

, Cheng

, Lin

. Progressive exercise preconditioning protects against circulatory shock during experimental heatstroke. Shock 2005;23:426–33

88.

Mizzen

, Welch

. Characterization of the thermotolerant cell. I. Effects on protein synthesis activity and the regulation of heat-shock protein 70 expression. J Cell Biol 1988;106:1105–16

89.

Struthers

, Quigley

, Brown

. Rapid change in plasma potassium during a game of squash. Clin Sci (Lond) 1988;74:397–401

90.

Whiticar

, Laba

, Smith

. Exertional heat stroke in a young man with a documented rise in troponin I. Emerg Med J 2008;25:283–4

91.

Cohen

, Moelleken

. Disorders due to physical agents. In: Tierney

, McPhee

, Papadakis

, eds. Current Medical Diagnosis and Treatment. New York: Lange, 2004:1533–4

92.

Pfeiffer

, Reinsberg

, Rahmun

, Schmolling

, Krebs

. Clinical application of maternal serum cytokine determination in premature rupture of membranes – interleukin-6, an early predictor of neonatal infection. Acta Obstet Gynecol Scand 1999;78:774–8

93.

Herzum

, Renz

. Inflammatory markers in SIRS, sepsis and septic shock. Curr Med Chem 2008;15:581–7

94.

Graogan

, Hopkins

. Heatstroke: implications for critical care and anesthesia. Br J Anaesth 2002;88:700–7

95.

Smith

. Cooling methods used in the treatment of exertional heat illness. Br J Sports Med 2005;39:503–7

96.

Ward

, Chaffman

, Sorkin

. Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity. Drugs 1986;32:130–68

97.

Green

, O'Shea

, Colado

. A review of the mechanisms involved in the acute MDMA (ecstasy)-induced hyperthermic response. Eur J Pharmacol 2004;500:3–13

98.

Adubofour

, Kajiwara

, Goldberg

, King-Angell

. Oxybutynin-induced heatstroke in an elderly patient. Ann Pharmacother 1996;30:144–7

99.

Rusyniak

, Sprague

. HYperthermic Syndromes Induced by Toxins. Clin Lab Med 2006;26:165

100.

Milroy

, Clark

, Forrest

. Pathology of deaths associated with “ecstasy” and “eve” misuse. J Clin Pathol 1996;49:149–53

101.

Rosenberg

, Davis

, James

, Pollock

, Stowell

. Malignant hyperthermia. Orphanet J Rare Dis 2007;2:21

Clinical biochemistry of hyperthermia

Abstract

Introduction

Scope

Climate change

Physiology

Pathogenesis

Cytokines

Heat shock proteins

Thermo-tolerance and acclimatization

Biochemical findings associated with heatstroke

Acid–base status

Renal function tests

Cardiac and skeletal muscle markers

Liver injury and dysfunction tests

C-reactive protein

Procalcitonin

Metabolic markers

Therapeutic measures

Drugs

Future studies

Conclusion

DECLARATIONS

References