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Abstract

Heatstroke represents the most severe end of the heat illness spectrum, and is increasingly seen in those undergoing exercise or exertion (‘exertional heatstroke’) and those exposed to high ambient temperatures, for example in heatwaves (‘classical heatstroke’). Both forms may be associated with significant thermal injury, leading to organ dysfunction and the need for admission to an intensive care unit. The process may be exacerbated by translocation of bacteria or endotoxin through an intestinal wall rendered more permeable by the hyperthermia. This narrative review highlights the importance of early diagnosis, rapid cooling and effective management of complications. It discusses the incidence, clinical features and treatment of heatstroke, and discusses the possible role of intestinal permeability and advances in follow-up and recovery of this condition. Optimum treatment involves an integrated input from prehospital, emergency department and critical care teams, along with follow-up by rehabilitation teams and, if appropriate, sports or clinical physiologists.

Keywords

Heatstroke hyperthermia exertional heat illness multiple organ failure therapy

Introduction

Heatstroke represents the extreme and life-threatening end of the spectrum of heat-related illness. Heat illness is common; it is responsible for tens of thousands of deaths in heatwaves,¹ is predicted to rise by over 2.5-fold in the next 30 years,² and is in the top three causes of deaths in athletes.³

Heatstroke is often a multi-system disease, commonly causing coagulopathy, respiratory failure, renal and liver injury, and gastrointestinal dysfunction. If severe, organ support in an intensive care unit (ICU) may be required. Mortality is high, up to 80% if untreated,⁴ and is related to the duration and extent of the hyperthermia and the degree of organ dysfunction.⁵ In patients requiring critical care, mortality may still be above 60%.⁵

Optimal outcomes are likely to require prompt recognition and immediate treatment by prehospital, emergency medical and critical care teams, followed by effective rehabilitation and sports exercise medicine input as required.

With the UK recently experiencing its highest recorded temperature, this narrative review describes its presentation, the need for immediate cooling and supportive care, and the associated morbidity and risks. It also describes some of the new findings around the mechanism, risk factors predisposing to its development, and the need for long-term follow-up and guidance to survivors.

Definition

The most commonly used and widely known definition of heatstroke was originally proposed by Bouchama and Knochel,⁶ defined as a core body temperature greater than 40°C associated with central nervous system (CNS) dysfunction, such as delirium, convulsions or coma. An alternative definition has been proposed by the Japanese Association for Acute Medicine (JAAM), which defines heatstroke as patients exposed to high environmental temperature, with one or more of the following:

disseminated intravascular coagulopathy,

CNS manifestation (impaired consciousness, cerebellar symptoms, convulsive seizures), or

hepatic or renal impairment.⁷

The JAAM defines heatstroke as the most severe (Stage 3) of three heat illness categories, with heat cramp (e.g. dizziness and muscle cramps) representing Stage 1 and heat exhaustion (e.g. headache and vomiting) Stage 2. Core body temperature is not included in the diagnostic criteria; several fatal cases have been reported where the core body temperature was less than 40°C,⁷ and good tolerance of core temperatures above 40°C can be observed in trained athletes.

This article will concentrate on heatstroke; other heat illnesses lie outside the scope of this review.

Subtypes of heatstroke

There are two subtypes of heatstroke, both relating to the inability to dissipate excessive body heat, unlike a pyrexia accompanying an infection, where the hypothalamic thermoregulatory setpoint is increased.

Classical heatstroke (CHS)

This is due to passive heat exposure with poor dissipation mechanisms and is typically seen during heat waves in those considered more vulnerable, such as the elderly, those with underlying health conditions associated with a reduced thermoregulatory capacity, or pre-pubertal children.

Exertional heatstroke (EHS)

This typically occurs in otherwise healthy individuals undertaking vigorous exertion, such as endurance sporting events and military activity, and in certain occupational workers, such as riot police and fire personnel. Unlike in CHS, in EHS, large quantities of heat are produced from skeletal muscle activity; it can therefore occur at low ambient temperatures.⁸

Risk factors for heatstroke

A number of factors predispose to the development of heatstroke (Table 1), which has been adapted from a review article discussing drugs that may increase the risk of hyperthermia and the purported mechanisms⁹. In one series, over 57% of patients with CHS had been taking at least one drug known to increase the risk of heat illness,¹⁰ such as diuretics and antihypertensive treatment affecting blood flow and heat loss, and antipsychotic and antidepressant medications that can further increase heat gain.

Table 1.

Conditions and medications that may increase the risk of heatstroke.

Extrinsic causes	Intrinsic causes	Medications increasing the risk of heat illness
• Hot, humid conditions • Heatwaves • Lack of heat acclimatisation • Cumulative effect of heat exposure • Inappropriate clothing • Lack of fans/air conditioning	• Low physical fitness levels • Obesity • Underlying medical conditions: diabetes, skin disorders, sickle cell trait and cardiovascular disease • Concurrent infections • Extremes of age • Male sex • Disturbed sleep patterns • Hydration status • Poor nutrition • Previous episode of heat illness • Dehydration • High levels of physical exertion • Genetic predisposition	• Alcohol • Amphetamines • Anticholinergic and sympathomimetic agents • Antihistamines • Benzodiazepines • Beta blockers • Calcium channel blockers • Cocaine • Diuretics • Laxatives • Neuroleptic medications • Phenothiazines • Thyroid agonists • Tricyclic antidepressants

Presentation and progression of disease

Clinical features

Patients typically present with the following features:

Core body temperature > 40.0°C

Malaise, fatigue, dizziness, nausea, vomiting, headache, fainting, weakness and heavy sweating

Limbs paradoxically cool and clammy (peripherally shut down)

Tachycardia, hypotension

Neurological impairment (irritability, ataxia, confusion, coma).

Heatstroke is a systemic disorder that can also lead to multi-organ dysfunction, within around 48 h of presentation.

Neurological system

Neurological dysfunction is a cardinal feature of heatstroke. Patients may present with various forms of neurological impairment, which may manifest as behavioural changes, confusion, lethargy, delirium or weakness; more severe features include seizures and alteration in levels of consciousness.¹¹

Cardiovascular system

Tachycardia is commonly seen, and is often associated with an increased cardiac output, peripheral vasodilatation and hypovolaemia acutely. Shock may be present, in up to 43% of patients.¹² The pathogenesis of the shock is not yet fully elucidated, but may be due to redistribution of blood from the central intravascular circulation to the periphery in an attempt to lose heat, direct myocardial injury from the thermal stress, or from nitric oxide-induced vasodilatation. Hypodynamic shock with decreased cardiac output and increased peripheral and pulmonary vascular resistance has also been observed, particularly in CHS. Electrocardiographic changes during heatstroke are common, and include malignant tachyarrhythmias, conduction defects, prolongation of the QT interval, ST changes and T wave abnormalities.¹³

Respiratory system

Tachypnoea is a consistent feature in patients with heatstroke, due partly to heat-induced hyperventilation, of unclear aetiology. This may progress to respiratory failure, reported in 47% of patients,¹² requiring endotracheal intubation and mechanical ventilation in around 20% of patients.¹⁴

Renal system

Renal dysfunction varies from mild proteinuria to acute kidney injury (AKI); of heatstroke patients hospitalised with CHS during the 1995 Chicago heatwave, 53% had at least moderate renal impairment.¹⁵ AKI is more common in EHS than CHS, affecting 91% of patients in one series,¹⁶ and may require renal replacement therapy (RRT). Rhabdomyolysis, with its associated complications, is observed in exercise and in heat illness, where it may be related to an underlying genetic susceptibility.

Hepatic system

Abnormal liver function may be seen, and can in rare cases progress to acute liver failure, particularly in patients with EHS. Early mild elevations in aspartate aminotransferase and lactate dehydrogenase are seen, followed by a rise in bilirubin on the second or third day after the heat insult.

Haematological system

Coagulation disturbances range from petechial haemorrhage and ecchymosis to a severe disseminated intravascular coagulation picture.

Prognostic factors

Short-term outcomes

Several studies have identified factors associated with increased mortality and morbidity in both non-exertional and exertional heatstroke patients. Unsurprisingly, frailer patients and those with more significant organ dysfunction, such as coagulopathy,^5,17 hypotension,^5,17,18 renal failure¹⁷ and hypoxaemia¹⁸ have a worse outcome. The extent and duration of the hyperthermia also predicts outcome,^5,19,20 necessitating emergent and rapid cooling (see below).

Long-term outcomes

A number of factors appear to affect prognosis (see Table 2). In one single observational study of 1456 patients admitted with heat illness in the Paris 2003 heatwave, the presence of particular risk factors in combination reduced the 1-year survival rate from 85% to 18%.²¹

Table 2.

Prognostic factors affecting long-term outcomes following heatstroke.

Country	Population	No. of patients	Outcome	Prognostic feature	Reference
France	Non-exertional heatstroke (core body temperature > 38.5°C)	1456	1-year mortality	• Previous treatment with diuretics	Hausfater et al.²¹
				• Living in an institution
				• Age > 80 years
				• Presence of cardiac disease or cancer
				• Core body temperature > 40°C
				• SBP < 100 mmHg
				• GCS score < 12
				• Requiring transportation to hospital in ambulance
France	Non-exertional heatstroke (core body temperature > 40°C)	83	2-year mortality	• Living at an institution	Argaud et al.¹²
				• The use of long-term antihypertensive medication
				• Presence of anuria, coma, or cardiovascular failure at admission

Survivors may be at risk of long-term complications. In one study of CHS patients, the 28-day mortality was 58%, but had risen to 71% by 2 years.¹² At 1-year follow-up, the proportion of survivors with severe limitation in activity, defined as being unable to work or institutionalised, had risen from 3.7% to 40.7%.¹²

The risk of developing ischaemic heart disease after heatstroke increases by 3.5-fold at 12 years²² and acute myocardial infarction 2.7-fold compared to matched controls in a group of Taiwanese patients.²² The risk of heart failure is increased by 26-fold at 14 years.²³

Persistent neurological dysfunction has been observed in up to 66% of survivors in one study.¹⁵ The cerebellum is frequently affected in cases of persistent neurological dysfunction, given the extreme sensitivity of Purkinje fibres to hyperthermia.²⁴ However, persistent damage to many other parts of the brain has also been reported.¹¹

Pathophysiology

A number of mechanisms for organ damage in heatstroke are proposed (see Figure 1).

Figure 1.

Proposed mechanisms of systemic dysfunction in hyperthermia. Adapted from Walter et al.²⁵

Hyperthermia is directly cytotoxic, affecting membrane stability, transmembrane transport protein function, leading to intracellular electrolyte derangement. Protein, RNA and DNA synthesis is impaired, with the latter disrupted for longer.²⁶ Direct cell death in humans occurs at temperatures of around 41°C.²⁶ The thermal energy required for cell death is similar to that required for protein denaturation, suggesting that hyperthermic cell death occurs primarily through its effect on protein structure.²⁶ The cellular and surrounding microenvironment is susceptible to direct thermal damage after only a short period; interstitial changes occur after only 30 min at 40.5°C.²⁷

In addition to direct thermal damage, organ dysfunction may be due to hyperthermic damage rendering the intestinal barrier more permeable, allowing intestinal toxins such as bacteria,²⁸ endotoxin and lipopolysaccharides (LPS)²⁹ to enter the systemic circulation. Changes to the intestinal permeability can occur at modest temperatures, around 39°C,³⁰ and after a short period of hyperthermia, 1–2 h.³⁰ Intestinal permeability increases have been observed in humans during exertional hyperthermia.^31,32 Endotoxaemia and raised LPS levels are thought to be responsible for the inflammatory response and stimulation of inflammatory mediators in both CHS and EHS.³³

Changes in interleukin levels show some correlation with outcome; the rise in IL-6 and the duration of the increased expression is related to mortality in one study, independent of the maximum core temperature obtained.³⁴ In an animal study, pre-treatment with IL-6 before exposure to heat and antagonism of IL-1, a pro-inflammatory cytokine, improves survival.³⁵

Mechanisms of cerebral damage

Additional mechanisms for hyperthermic cerebral dysfunction are proposed. The permeability of the blood-brain barrier increases at temperatures above 38–39°C,³⁶ exposing the brain to systemic and intestinal toxins, such as LPS³⁷ (‘gut-brain axis’). Cerebral oxygen and glucose consumption is reduced, either due to impaired cellular uptake or reduction in cerebral metabolic activity.³⁸ Cerebral blood flow, while it initially increases,³⁹ falls to baseline or below at temperatures above 40–41°C.^38,40

Synergistic effects of heat and exercise

Combining hyperthermia and exertion, such as in EHS, has synergistic effects. Intestinal permeability in exertional heat stress is higher than in exertion at normothermia³¹ or passive hyperthermia alone.³²

Treatment of hyperpyrexia

Optimal treatment of heatstroke is currently based around immediate and rapid cooling and supportive care, which may include organ support in an ICU setting. No drugs are currently recommended routinely.

Physical cooling

Rapid cooling in patients with heatstroke, regardless of the underlying cause, improves mortality. In CHS, the mortality of those cooled to a core temperature of below 38.9°C within an hour of presentation more than halves, compared to those who remain above 38.9°C.¹⁹ Cooling rates of greater than 0.15°C/min reduce mortality in EHS.²⁰ Rapid cooling should therefore begin on-site as soon as possible and prior to transfer. A target core temperature of 38.6°C has been suggested, to avoid hypothermia through over-cooling.⁴¹ Core temperature (e.g. rectal) measurement is more accurate than peripheral measurement, and is recommended.⁴² Additional passive cooling measures include moving the patient out of direct sunlight and removing constrictive clothing.

A variety of active cooling measures can be deployed (Figure 2), depending on the setting and resources available. In EHS, cooling by immersion in cold water is the most effective and rapid,⁴³ and is recommended.⁴⁴ Public events with an increased risk of exertional heat illness often have facilities available for cold-water immersion (CWI) therapy on site. Cooling with water via dousing or tarp-assisted approaches are effective in the absence of CWI. Spraying the patient with a mist of water whilst fans blow air over the moistened skin is also effective; ice packs are less effective in isolation and pose the risk of local tissue damage but may be used in combination with other techniques.⁴⁵ These techniques may be easier to facilitate than CWI, especially when faced with multiple casualties.

Figure 2.

Rates of cooling for specific methods. Data from McDermott et al.⁴³

Cold (4°C) intravenous fluids may be used as an adjunct to the primary cooling techniques but should not be relied on as a sole method of cooling. There is no strong evidence for a particular resuscitation fluid; however, 0.9% saline may be preferred in EHS if there is an associated exercise-induced hyponatraemia. Although newer devices to aid active cooling have been developed, such as intranasal cooling, endovascular cooling catheters, and blankets made from high heat-conductive biomaterials, their use and effectiveness remain to be validated.

Supportive therapy

Despite rapid cooling, some patients with heatstroke develop multi-organ failure and require admission to an ICU. Patients may require critical care support immediately on presentation; alternatively, organ dysfunction may worsen in the first few days,⁵² necessitating delayed admission.

Organ dysfunction in heatstroke is generally managed conventionally. Specific aspects of management are detailed below.

Optimum temperature target after the initial cooling is unclear. A temperature of 37.5°C or above has a trend towards reduced survival in critically ill non-infective patients compared with 36.5–37.4°C, becoming significant above 38.5°C, suggesting a core temperature below 37.5°C may be prudent after the initial cooling.⁵³

Patients may require intubation for airway protection, respiratory failure or neurological dysfunction. Agitation may warrant the use of sedation, with benzodiazepines suggested to have a theoretical benefit in blunting the shivering reflex and reducing oxygen consumption.⁵⁴ Arterial blood gases may be difficult to interpret in hyperthermia, due to changes in solubility and dissociation with haemoglobin.⁵⁵

Cardiovascular dysfunction may be multi-faceted, and require management of dehydration, cardiogenic and vasoplegic shock. In addition, both hypernatraemia and hyponatraemia may be seen in EHS, warranting close electrolyte monitoring. There is no evidence to advise alternative management to conventional treatment.

Liver dysfunction may be severe enough to warrant assessment for transplantation. Standard referral criteria are advised for liver transplantation, although one series reports that as three out of four transplant recipients did not survive and that there was spontaneous recovery in two-thirds, a more conservative approach might be warranted.⁵⁶ A prothrombin time of more than 10 times normal, persisting after 3 days, has been suggested as a further criterion for transplantation.⁵⁷ The AKI may be severe enough to require RRT. RRT in heatstroke with multi-organ failure may improve survival and a faster return to normal of serum markers and organ function, independent of the renal failure.⁵⁸ Measurement of creatine kinase levels is advised, to detect rhabdomyolysis.

Patients may be at higher risk of infection, which could be related to gastrointestinal permeability. In one study, over 50% of CHS patients showed evidence of bacterial infections.¹⁵ In a further study, procalcitonin, which has a high sensitivity and specificity for detecting bacteraemia, was elevated in 58% of patients with CHS and was associated with increased mortality.⁵⁹

During recovery, regular assessment of arterial blood gases, full blood count, biochemistry and coagulation is important; blood tests typically return to normal within 16 days, despite different recovery kinetics.⁵²

On discharge from ICU, survivors may benefit from follow-up with general medical and rehabilitation teams; if they recover well, advice from a geneticist, and sports or clinical physiologist may be beneficial (see below).

Pharmacological management

Dantrolene is used in the management of MH to reduce excessive muscle contraction and heat production. While there are similarities between EHS and MH, dantrolene is not currently routinely recommended in heatstroke⁶⁰; however, the authors of this study suggest its use may be rational in severe cases or in cases where no improvement is observed after cooling.⁶⁰

Although antipyretics such as ibuprofen, aspirin and paracetamol may be useful in sepsis-induced pyrexias, the mechanism of the pyrexia in heatstroke is different. Antipyretics are therefore not advised and may worsen the associated coagulopathy, and hepatic and renal injury.⁶¹

Recent systematic reviews have suggested that both systemic steroids and antibiotics against intestinal bacteria may be effective in reducing intestinal bacterial translocation, inflammatory response, organ dysfunction and mortality in heatstroke.^62,63 Trials are ongoing, but neither are currently recommended.

Future work, follow-up and recovery

Individuals who recover may be at risk of a future episode of heat illness. After an episode of EHS, the risk of a further episode has been reported as over three times higher within the first 2 years.⁶⁴ Whether this is related to pre-existing genetic, phenotypic or behavioural risks, or post-exposure biochemical or genetic changes is not clear.

While follow-up of patients is currently very limited, the following areas may need to be considered.

Return to play guidelines after EHS

Some authorities recommend that in the first 14–21 days following exertional heat illness, an individual is confined to rest and essential activities of daily living before progressing to low-intensity activity in cool conditions to ensure exercise can be tolerated.^42,65 Medical assessment may be an occupational requirement prior to the commencement of any exercise.⁶⁵

Once exercise in cooler conditions can be tolerated, intensity can increase and thermal stress added. To maximise resistance to heat, a full heat acclimation/acclimatisation protocol may be warranted⁶⁶; advice from a sports physiologist may be beneficial.

Heat tolerance testing

The use and optimal approach of exercise-heat stress tests to further guide return to fitness remains uncertain.^42,65 A typical heat tolerance test is one created by the Israeli Defence force, which currently requires participants to walk at 5 km/h at a 2% gradient for 120 min in conditions of 40°C and 40% relative humidity, 6–8 weeks following heat illness.⁶⁷ Testing is discontinued and the participant deemed heat intolerant if core temperature surpasses 38.5°C or the heart rate exceeds 145 beats per minute.⁶⁷ Reassessment follows 2–3 months later.

Genetic abnormalities in heatstroke

Exertional heatstroke has clinical and biochemical similarities to malignant hyperthermia (MH), with case reports of patients with both conditions. Mutations in the ryanodine receptor (RYR), which mediates cellular calcium release, account for the majority of MH cases.⁶⁸ Some patients with EHS also display mutations in the RYR1 gene⁶⁹; some authorities therefore advise consideration for testing for susceptibility for MH,⁷⁰ especially if the EHS is recurrent or if no other obvious precipitant is identified.⁷¹

The genetic basis of EHS may be more heterogeneous than MH; mutations in the sarcoplasmic skeletal muscle protein calsequestrin (CASQ1), which appears to modulate RYR1 function, and in the TrpV1 gene, involved with detecting and sensing thermoregulation and nociception, have been identified.^72,73

Role of diet

A number of nutritional components, such as vitamins A and D, probiotics, arginine and glutamine appear to improve intestinal barrier function, raising the possibility of manipulating the risk of developing heat illness in high-risk individuals. Further research on the clinical significance is warranted.

Conclusion

Heatstroke, either exertional or environmental, is a common syndrome and becoming commoner. In a world where heat waves may become increasingly frequent, heatstroke is a condition with which critical care clinicians should be familiar. The priorities are urgent diagnosis, immediate cooling and supportive care, which may include multi-organ support in ICU. It is associated with a significant risk of multi-organ failure and death, even with intensive care. There is a role for further research in this area given the current paucity of high-level evidence, which would help identify individuals at risk, improve follow-up and offer advice for recovery, return to fitness and reducing future risk. There is interest in the effect of intestinal dysfunction and translocation of intestinal toxins, and whether these may be affected to reduce the effects of heat illness.

Footnotes

Acknowledgements

Figure 1, taken from Walter EJ, Hanna-Jumma S, Carraretto M, Forni LG. The pathophysiological basis and consequences of fever. Crit Care. 2016; 20: 200. https://doi.org/10.1186/s13054-016-1375-5 and published by Springer Nature, is reproduced under the terms of the Creative Commons Attribution 4.0 International Licence ().

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Daniel Martin is Editor-in-Chief of the Journal of the Intensive Care Society. Edward Walter is on the editorial board of the Journal of the Intensive Care Society. No other authors declare a conflict of interest.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Jesal Patel

Edward Walter

References

World Health Organization. Heat and Health, https://www.who.int/news-room/fact-sheets/detail/climate-change-heat-and-health (2018, accessed 23 March 2022).

Hajat

Vardoulakis

Heaviside

, et al. Climate change effects on human health: projections of temperature-related mortality for the UK during the 2020s, 2050s and 2080s. J Epidemiol Community Health 2014; 68: 641–648.

Howe

Boden

. Heat-related illness in athletes. Am J Sports Med 2007; 35: 1384–1395.

Mahant

. The evaluation and management of heat injuries in an intensive care unit. Indian J Crit Care Med 2015; 19: 479–483.

Misset

De Jonghe

Bastuji-Garin

, et al. Mortality of patients with heatstroke admitted to intensive care units during the 2003 heat wave in France: a national multiple-center risk-factor study. Crit Care Med 2006; 34: 1087–1092.

Bouchama

Knochel

. Heat stroke. New Engl J Med 2002; 346: 1978–1988.

Hifumi

Kondo

Shimizu

, et al. Heat stroke. J Intensive Care 2018; 6: 1–8.

Robertson

Walter

. ‘Cool runnings’: heat stroke in cool conditions. Emerg Med J 2010; 27: 387–388.

Walter

Carraretto

. Drug-induced hyperthermia in critical care. J Intensive Care Soc 2015; 16: 306–311.

10.

Jiménez-Mejías

Montaño Díaz

Villalonga

, et al. [Classical heatstroke in Spain. Analysis of a series 78 cases]. Med Clin 1990; 94: 481–486.

11.

Walter

Carraretto

. The neurological and cognitive consequences of hyperthermia. Crit Care 2016; 20: 199.

12.

Argaud

Ferry

Q-H

, et al. Short- and long-term outcomes of heatstroke following the 2003 heat wave in Lyon, France. Arch Intern Med 2007; 167: 2177–2183.

13.

Paul

Alex

Jacob

, et al. Effects of heat stroke on surface ECG: a study on clinical outcomes. Heart Asia 2019; 11: e011221.

14.

Kaewput

Thongprayoon

Petnak

, et al. Inpatient burden and mortality of heatstroke in the United States. Int J Clin Pract 2021; 75: e13837.

15.

Dematte

O'Mara

Buescher

, et al. Near-fatal heat stroke during the 1995 heat wave in Chicago. Ann Intern Med 1998; 129: 173–181.

16.

Satirapoj

Kongthaworn

Choovichian

, et al. Electrolyte disturbances and risk factors of acute kidney injury patients receiving dialysis in exertional heat stroke. BMC Nephrol 2016; 17: 55.

17.

Hifumi

Kondo

Shimazaki

, et al. Prognostic significance of disseminated intravascular coagulation in patients with heat stroke in a nationwide registry. J Crit Care 2018; 44: 306–311.

18.

Tsuruta

Aruga

Inoue

, et al. Predictors of poor outcome in mechanically ventilated patients due to heat-related illness. J Japanese Assoc Acute Med 2010; 21: 786–791.

19.

Vicario

Okabajue

Haltom

. Rapid cooling in classic heatstroke: effect on mortality rates. Am J Emerg Med 1986; 4: 394–398.

20.

Filep

Murata

Endres

, et al. Exertional heat stroke, modality cooling rate, and survival outcomes: a systematic review. Medicina 2020; 56: 589.

21.

Hausfater

Megarbane

Dautheville

, et al. Prognostic factors in non-exertional heatstroke. Intensive Care Med 2010; 36: 272–280.

22.

Tseng

Chou

Chung

, et al. Association between heat stroke and ischemic heart disease: a national longitudinal cohort study in Taiwan. Eur J Intern Med 2019; 59: 97–103.

23.

Wang

Chien

Chu

, et al. The association between heat stroke and subsequent cardiovascular diseases. PLoS One 2019; 14: e0211386.

24.

Bazille

Megarbane

Bensimhon

, et al. Brain damage after heat stroke. J Neuropathol Exp Neurol 2005; 64: 970–975.

25.

Walter

Hanna-Jumma

Carraretto

, et al. The pathophysiological basis and consequences of fever. Crit Care 2016; 20: 200–210.

26.

Hildebrandt

Wust

Ahlers

, et al. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol 2002; 43: 33–56.

27.

Vlad

Ionescu

Ispas

, et al. Morphological changes during acute experimental short-term hyperthermia. Rom J Morphol Embryol 2010; 51: 739–744.

28.

Liu

, et al. Reduction of intestinal mucosal immune function in heat-stressed rats and bacterial translocation. Int J Hyperthermia 2012; 28: 756–765.

29.

Hall

Buettner

Oberley

, et al. Mechanisms of circulatory and intestinal barrier dysfunction during whole body hyperthermia. Am J Physiol 2001; 280: H509–H521.

30.

Dokladny

Moseley

. Physiologically relevant increase in temperature causes an increase in intestinal epithelial tight junction permeability. Am J Physiol 2006; 290: G204–G212.

31.

Walter

Gibson

Stacey

, et al. Changes in gastrointestinal cell integrity after marathon running and exercise-associated collapse. Eur J Appl Physiol 2021; 121: 1179–1187.

32.

Walter

W Watt

Gibson

, et al. Exercise hyperthermia induces greater changes in gastrointestinal permeability than equivalent passive hyperthermia. Physiol Rep 2021; 9: e14945.

33.

Heled

Fleischmann

Epstein

. Cytokines and their role in hyperthermia and heat stroke. J Basic Clin Physiol Pharmacol 2013; 24: 85–96.

34.

Hashim

Al-Zeer

Al-Shohaib

, et al. Cytokine changes in patients with heatstroke during pilgrimage to Makkah. Mediators Inflamm 1997; 6: 135–139.

35.

Chiu

W-T

Kao

T-Y

Lin

M-T

. Interleukin-1 receptor antagonist increases survival in rat heatstroke by reducing hypothalamic serotonin release. Neurosci Lett 1995; 202: 33–36.

36.

Kiyatkin

Sharma

. Permeability of the blood-brain barrier depends on brain temperature. Neuroscience 2009; 161: 926–939.

37.

Peng

Luo

, et al. Blood-brain barrier disruption by lipopolysaccharide and sepsis-associated encephalopathy. Front Cell Infect Microbiol 2021; 11: 768108.

38.

Cremer

Kalkman

. Cerebral pathophysiology and clinical neurology of hyperthermia in humans. Prog Brain Res 2007; 162: 153–169.

39.

Busija

Leffler

Pourcyrous

. Hyperthermia increases cerebral metabolic rate and blood flow in neonatal pigs. Am J Physiol 1988; 255: H343–H346.

40.

Qian

Jiang

Liu

, et al. Effects of short-term environmental hyperthermia on patterns of cerebral blood flow. Physiol Behav 2014; 128: 99–107.

41.

Gagnon

Lemire

Casa

, et al. Cold-water immersion and the treatment of hyperthermia: using 38.6°C as a safe rectal temperature cooling limit. J Athl Train 2010; 45: 439–444.

42.

Roberts

Armstrong

Sawka

, et al. ACSM expert consensus statement on exertional heat illness: recognition, management, and return to activity. Curr Sports Med Rep 2021; 20: 470–484.

43.

McDermott

Casa

Ganio

, et al. Acute whole-body cooling for exercise-induced hyperthermia: a systematic review. J Athl Train 2009; 44: 84–93.

44.

Walter

Galloway

Stacey

, et al. Exertional heatstroke (position statement): The Faculty of Sport and Exercise Medicine (FSEM) UK, https://www.fsem.ac.uk/position_statement/exertional-heat-stroke/ (2018, accessed 22 June 2022).

45.

Gaudio

Grissom

. Cooling methods in heat stroke. J Emerg Med 2016; 50: 607–616.

46.

Proulx

Ducharme

Kenny

. Effect of water temperature on cooling efficiency during hyperthermia in humans. J Appl Physiol 2003; 94: 1317–1323.

47.

Hadad

Moran

Epstein

. Cooling heat stroke patients by available field measures. Intensive Care Med 2004; 30: 338.

48.

Armstrong

Crago

Adams

, et al. Whole-body cooling of hyperthermic runners: comparison of two field therapies. Am J Emerg Med 1996; 14: 355–358.

49.

Wyndham

Strydom

Cooke

, et al. Methods of cooling subjects with hyperpyrexia. J Appl Physiol 1959; 14: 771–776.

50.

Kielblock

Van Rensburg

Franz

. Body cooling as a method for reducing hyperthermia: an evaluation of techniques. S Afr Med J 1986; 69: 378–380.

51.

Hart

Egier

Shimizu

, et al. Exertional heat stroke: the runner’s nemesis. Can Med Assoc J 1980; 122: 1144–1150.

52.

Ward

King

Gabrial

, et al. Biochemical recovery from exertional heat stroke follows a 16-day time course. PLoS One 2020; 15: e0229616.

53.

Lee

Inui

Suh

, et al. Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care 2012; 16: R33.

54.

Hostler

Northington

Callaway

. High-dose diazepam facilitates core cooling during cold saline infusion in healthy volunteers. Appl Physiol Nutr Metab 2009; 34: 582–586.

55.

Bacher

. Effects of body temperature on blood gases. Intensive Care Med 2005; 31: 24–27.

56.

Martins

Mcdaid

Hertl

, et al. Heat-stroke as a cause of liver failure and evaluation for liver transplant. Transplantation 2012; 94: 413.

57.

Ichai

Laurent-Bellue

Camus

, et al. Liver transplantation in patients with liver failure related to exertional heatstroke. J Hepatol 2019; 70: 431–439.

58.

Chen

Zhang

, et al. Therapy of severe heatshock in combination with multiple organ dysfunction with continuous renal replacement therapy: a clinical study. Medicine 2015; 94: e1212.

59.

Hausfater

Hurtado

Pease

, et al. Is procalcitonin a marker of critical illness in heatstroke? Intensive Care Med 2008; 34: 1377–1383.

60.

Hadad

Cohen-Sivan

Heled

, et al. Clinical review: treatment of heat stroke: should dantrolene be considered? Crit Care 2005; 9: 86–91.

61.

Grogan

Hopkins

. Heat stroke: implications for critical care and anaesthesia. Br J Anaesth 2002; 88: 700–707.

62.

Walter

Gibson

. The efficacy of steroids in reducing morbidity and mortality from extreme hyperthermia and heatstroke-a systematic review. Pharmacol Res Perspect 2020; 8: e00626.

63.

Walter

Gibson

. The efficacy of antibiotics in reducing morbidity and mortality from heatstroke - a systematic review. J Therm Biol 2020; 88: 102509.

64.

Stearns

Hosokawa

Adams

, et al. Incidence of recurrent exertional heat stroke in a warm-weather road race. Medicina 2020; 56: 720.

65.

Mitchell

Cheuvront

King

, et al. Use of the heat tolerance test to assess recovery from exertional heat stroke. Temperature 2019; 6: 106–119.

66.

Gibson

James

Mee

, et al. Heat alleviation strategies for athletic performance: A review and practitioner guidelines. Temperature 2020; 7: 3–36.

67.

Moran

Erlich

Epstein

. The heat tolerance test: an efficient screening tool for evaluating susceptibility to heat. J Sport Rehabil 2007; 16: 215–221.

68.

McCarthy

Quane

Lynch

. Ryanodine receptor mutations in malignant hyperthermia and central core disease. Hum Mutat 2000; 15: 410–417.

69.

Roux-Buisson

Monnier

Sagui

, et al. Identification of variants of the ryanodine receptor type 1 in patients with exertional heat stroke and positive response to the malignant hyperthermia in vitro contracture test. Br J Anaesth 2016; 116: 566–568.

70.

Malignant Hyperthermia Association of the United States and the North American Malignant Hyperthermia Registry of MHAUS. MHAUS recommendation: Adverse effects of heat and exercise in relation to MH susceptibility [Internet]. 2019; 37(3): 1–12. Available from: MHAUS_Communicator_Summer_2019.pdf (ymaws.com) (2019, accessed 22 June 2022).

71.

Hopkins

. Malignant hyperthermia: advances in clinical management and diagnosis. Br J Anaesth 2000; 85: 118–128.

72.

Protasi

Paolini

Dainese

. Calsequestrin-1: a new candidate gene for malignant hyperthermia and exertional/environmental heat stroke. J Physiol 2009; 587: 3095–3100.

73.

Bosson

Rendu

Pelletier

, et al. Variations in the TRPV1 gene are associated to exertional heat stroke. J Sci Med Sport 2020; 23: 1021–1027.

Critical illness aspects of heatstroke: A hot topic

Abstract

Keywords

Introduction

Definition

Subtypes of heatstroke

Classical heatstroke (CHS)

Exertional heatstroke (EHS)

Risk factors for heatstroke

Presentation and progression of disease

Clinical features

Neurological system

Cardiovascular system

Respiratory system

Renal system

Hepatic system

Haematological system

Prognostic factors

Short-term outcomes

Long-term outcomes

Pathophysiology

Mechanisms of cerebral damage

Synergistic effects of heat and exercise

Treatment of hyperpyrexia

Physical cooling

Supportive therapy

Pharmacological management

Future work, follow-up and recovery

Return to play guidelines after EHS

Heat tolerance testing

Genetic abnormalities in heatstroke

Role of diet

Conclusion

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

ORCID iDs

References