Heatstroke is a potentially fatal condition characterized by elevated body temperature and central nervous system (CNS) dysfunction. Impaired thermoregulation may arise from prolonged passive exposure to high temperatures, typically during heatwaves (classical heatstroke), or from intense physical exertion (exertional heatstroke). 

Exertional heatstroke (EHS) can affect athletes, military personnel, and workers. Excessive metabolic heat from skeletal muscle activity, combined with inadequate heat dissipation, leads to dangerous internal heat accumulation in the human body. 

EHS can occur even under mild or cold conditions. Because it arises in diverse settings, including amateur and professional sports, military training, and rescue operations, epidemiological data are fragmented and difficult to generalize.

The course of the EHS is highly time sensitive. Without rapid intervention, it can swiftly progress to multiple organ failure, with a mortality rate of up to 26.5%.

A recent review summarized the current evidence regarding the pathophysiology, diagnosis, and management of EHS by emergency physicians.

Key Mechanisms

Thermal Dysregulation and Cellular Damage

Sustained elevation of core temperature causes cytotoxic injury through direct damage to macromolecules and cellular structures, including protein and DNA denaturation and lipid membrane instability. 

This disruption impairs cellular metabolism and signaling. Structural damage extends to the cytoskeleton and organelles. Mitochondrial injury increases the production of reactive oxygen species, which further damages proteins, lipids, and DNA. 

Thermal toxicity leads to cell death via multiple pathways, including apoptosis, necroptosis, and ferroptosis.

Immune System Activation

Innate immunity serves as the body’s first line of defense against infections by detecting pathogen-associated molecular patterns through pattern recognition receptors (PRRs). 

Heat-induced cell necrosis releases damage-associated molecular patterns that activate PRRs. During heat stress, thermally induced breakdown of intestinal tight junctions, known as “leaky gut,” allows endotoxins and microbes to enter the systemic circulation, amplifying PRR-mediated signaling. 

This cascade activates the NF-kappa-B pathway and promotes the release of pro-inflammatory cytokines, such as interleukin (IL)-1 beta, IL-6, TNF-alpha, and IL-8. The concurrent production of anti-inflammatory cytokines indicates an overall dysregulated immune response rather than a purely pro-inflammatory response.

Organ Manifestations

CNS dysfunction is a hallmark of EHS and a key diagnostic criterion. 

The clinical features include confusion, disorientation, agitation, incoherent behavior, seizures, and coma. Neurological injury results from direct thermal damage, cytotoxic cerebral edema, blood-brain barrier disruption, and neuroinflammation.

Heat stroke-induced shock is multifactorial and may include hyperdynamic distributive shock, myocardial injury, and microcirculatory failure. 

Acute renal injury arises from hypoperfusion and may worsen with rhabdomyolysis or myoglobin deposition. 

Disseminated intravascular coagulation is common, and endothelial injury triggers tissue factor release and unregulated activation of the coagulation cascade, causing coagulopathy and thrombosis. 

Hepatocellular injury results from oxidative stress and microvascular thrombosis. Acute lung injury and pulmonary edema can result from endothelial dysfunction, widespread thrombosis, oxidative stress, and fluid overload.

Diagnostic Criteria

EHS is defined as a combination of hyperthermia and CNS dysfunction. Although a core temperature of 40 °C is included in the definition, there is no universal threshold, as severe complications can occur at lower temperatures depending on individual susceptibility. 

Conversely, some elite athletes can reach core temperatures above 40 °C without developing neurological symptoms, showing that elevated temperature alone does not confirm the diagnosis.

Cooling Priority

Rapid on-site cooling remains the gold standard treatment. Whole-body immersion in ice water, with the head kept above water, achieves the fastest reduction in core temperature — at least 0.15 °C/min. 

Cooling should stop when the core temperature reaches approximately 38 °C. Transport should begin only after substantial cooling, following the principle “cool first, transport later.” 

Currently, there is no effective pharmacological treatment for heatstroke. 

Critical Care

Emergency physicians can use a range of cooling systems originally designed for postcardiac arrest neuroprotection, including endovascular and intranasal devices, vests, helmets, pads, and blankets made of thermally conductive materials. Although these devices show potential, their effectiveness in EHS requires further investigation.

Critical care management focuses on managing complications such as acute lung injury, disseminated intravascular coagulation, renal failure, liver failure, and seizures. 

Liver failure requires close monitoring of coagulation and metabolic parameters, and transplantation should be considered in fulminant cases. 

Renal failure should be treated with aggressive fluid resuscitation, avoidance of nephrotoxic drugs, and renal replacement therapy if needed. 

Management of rhabdomyolysis includes volume replacement and urinary alkalinization with sodium bicarbonate to prevent myoglobin-induced nephrotoxicity.

Neurological symptoms are completely resolved in most patients after timely cooling and supportive care. Some survivors develop persistent cognitive and motor deficits that often involve the cerebellum. These individuals also face an increased long-term cardiovascular risk, possibly linked to the myocardial degeneration observed in preclinical studies.

EHS is a potentially life-threatening condition that requires prompt recognition and rapid intervention. Emergency physicians play a critical role across the entire chain of survival, from guiding prehospital care and implementing effective cooling strategies to managing complications in the intensive care unit and coordinating long-term rehabilitation.

This story was translated from JIM.