Heat stroke has not been universally defined, but researchers agree that the clinical symptoms of heat stroke include hyperthermia, systemic inflammation, multi-organ failure and disturbance of the central nervous system. The current model of heat stroke suggests that heat stroke is triggered by heat but driven by endotoxemia. Endotoxemia refers to an increase in gram-negative bacteria endotoxin, known as lipopolysaccharide (LPS), in the blood. Although the current model of heat stroke can explain the clinical presentation of heat stroke patients, the inconsistency of heat as a trigger of heat stroke, within and between individuals, remains unexplained. There is considerable overlap in the core temperature of heat stroke patients and that of healthy and conscious athletes at the end of endurance races. These observations suggest that heat stroke may not be triggered by heat, but by an intermediate pathway that can be activated under heat-stressed conditions. This thesis investigated a new model of heat stroke, known as the “dual pathway model,” which helps explain the pathophysiology of heat stroke.
This dual pathway model hypothesises that heat stroke is triggered by two separate, but sequentially connected pathways. The first pathway is triggered by endotoxemia. When endotoxemia can be tolerated or inhibited and heat exposure is prolonged, heat stroke can be triggered by a second pathway through the direct thermal effect of heat on cellular tissues. The dual pathway model postulates that heat intolerance is transient and results from a transient shift in physiological state in the form of immune disturbances that promote endotoxemia and systemic inflammation, and suppress the anti-LPS mechanisms. Prolonged intense exercise can induce these immune disturbances and cause in a state of transient heat intolerance. This thesis comprises a literature review and three studies.
The review of literature discussed the characterisation, and models of heat stroke. The epidemiology of heat stroke in the civilian, athlete and military populations was also discussed. The complication of using core temperature as an indicator of the risk of heat stroke was discussed and the evidence suggests that core temperature is best used as an indicator of total heat load, and not the risk of heat stroke. Although core temperature may not trigger heat stroke consistently, core temperature appears to inhibit exercise consistently at a critical point, which may function as a protective mechanism against heat stroke. The review also discussed evidence showing immune disturbances that occur during intense exercise. These immune disturbances were similar to, but of a lower magnitude than, the symptoms observed in heat stroke patients. The evidence supports the hypothesis that exercise-induced immune disturbances exists on the same continuum as the pathway of heat stroke. An exaggeration of exercise-induced immune disturbances can trigger the pathway of heat stroke.
Study I investigated leukocyte subset responses to moderate intensity exercise under heat stress. In a repeated-design study, 13 soldiers performed 3 h of moderate intensity exercise under heat stress conditions consuming either water or a carbohydrate drink. Moderate intensity exercise in the heat induced the same pattern and magnitude of leukocyte and subset responses as those observed during intense exercise in cool conditions. Prolonged exposure to these immune cell changes may lead to chronic immune suppression. Matching work intensity to physical fitness may be more important in preventing immune suppression than carbohydrate ingestion during moderate intensity exercise in the heat.
Study II investigated the hypothesis that overload training compromises heat tolerance by promoting LPS translocation and pro-inflammatory cytokine responses, and by suppressing the anti-LPS antibodies during exercise in the heat. Eighteen trained athletes were matched and randomly assigned to a normal training group, comprising two weeks of routine training, or to an overload training group, comprising a 20% increase in training volume during the same period. Both groups performed a heat-stress test before (Trial 1) and after (Trial 2) the two-week training intervention. Increasing training volume by two weeks was well-tolerated by the subjects. Running in the heat for 30–90 min at 70% VO2max can cause the same degree of endotoxemia as in a marathon. In the absence of overtraining, overload training decreased plasma LPS response at rest and during exercise in the heat. Compared with routine training, overload training resulted in lower plasma LPS concentration at rest and during recovery, but not during exercise. A well-tolerated overload training regimen can prevent a significant increase in pro-inflammatory cytokine during exercise in the heat.
Study III investigated the hypothesis that heat stroke can be triggered by endotoxemia or heat-induced tissue damage, and that pre-existing inflammation compromises heat tolerance, whereas blocking endotoxemia increases heat tolerance. In groups of eight, Wistar rats were treated with heat exposure only (HE), and heat exposure with one of the following treatments: turpentine (TPHE), dexamethasone (DXHE), combination of turpentine and dexamethasone (TPDXHE), and TPDXHE with polymyxin B (PMBHE). These rats were heat-stressed until the core temperature (Tc) was 42 ºC for 15 min. The TPHE, DXHE and TPDXHE rats were paired with equal-sized groups of rats given the same treatment, but without heat stress (TP, DX and TPDX, respectively). Inhibition of endotoxemia protected the DXHE and PMBHE rats from heat stroke, but not the TPDXHE rats. The TPDXHE rats had a higher degree of tissue damage with no increase in plasma LPS concentration. Mortality and symptoms of heat stroke occurred in the TPHE, HE and TPDXHE rats, but endotoxemia was observed only in the TPHE and HE rats. Pre-existing inflammation (TPHE) enhanced the pro-inflammatory cytokine response and tissue damage during heat stress.
The results of these studies support the hypothesis of the dual pathway model of heat stroke by showing that exercise in the heat can induce immune changes that, if prolonged, can lead to chronic immune suppression, and can cause endotoxemia in humans. The data also show that a tolerable increase in training volume suppresses plasma LPS concentration and pro-inflammatory cytokine responses, and increases the anti-LPS antibody response during exercise in the heat. Heat stroke can occur independently through the effects of endotoxemia or thermal effects of heat on cellular tissues. Having a pre-existing inflammation compromises heat tolerance, but the blocking of endotoxemia protects against heat stroke.